Publications by authors named "Sanjeev Kumar Srivastava"

17 Publications

  • Page 1 of 1

Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer.

Sci Rep 2021 Jun 18;11(1):12901. Epub 2021 Jun 18.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, USA.

Late diagnosis, unreliable prognostic assessment, and poorly-guided therapeutic planning result in dismal survival of ovarian cancer (OC) patients. Therefore, identifying novel functional biomarker(s) is highly desired for improved clinical management. MYB is an oncogenic transcription factor with emerging functional significance in OC. Here we examined its clinicopathologic significance by immunohistochemistry and TCGA/GTex data analyses. Aberrant MYB expression was detected in 94% of OC cases (n = 373), but not in the normal ovarian tissues (n = 23). MYB was overexpressed in all major epithelial OC histological subtypes exhibiting the highest incidence (~ 97%) and overall expression in serous and mucinous carcinomas. MYB expression correlated positively with tumor grades and stages. Moreover, MYB exhibited race-specific prognostic association. Moderate-to-high MYB levels were significantly associated with both poor overall- (p = 0.02) and progression-free (p = 0.02) survival in African American (AA), but not in the Caucasian American (CA) patients. Consistent with immunohistochemistry data, we observed significantly higher MYB transcripts in OC cases (n = 426) than normal ovary (n = 88). MYB transcripts were significantly higher in all epithelial OC subtypes, compared to normal, and its greater levels predicted poor survival in AA OC, but not CA OC, patients. Thus, MYB appears to be a useful clinical biomarker for prognostication, especially in AA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-92352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213794PMC
June 2021

Exosomal Formulation Escalates Cellular Uptake of Honokiol Leading to the Enhancement of Its Antitumor Efficacy.

ACS Omega 2020 Sep 31;5(36):23299-23307. Epub 2020 Aug 31.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama 36617, United States.

Honokiol is a phytochemical isolated from the Magnolia plant. It exhibits significant antitumor activity against a variety of cancer cell types via targeting of critical mediators of tumor progression, stromal remodeling, and chemoresistance. However, poor bioavailability and inefficient tumor uptake remain some of the hurdles in its translation as a therapeutically useful drug. Here, we developed a nanoformulation of honokiol using mesenchymal stem cell-derived exosomes, which are nonimmunogenic and express surface markers to support their tumor-targeted delivery. Maximum entrapment of honokiol occurred when it was mixed in a 1:4 weight ratio with exosomes and subjected to six cycles of sonication. Dynamic light scattering analysis demonstrated that the average size (∼175.3 nm), polydispersity (∼0.11), and integrity (∼12.9 mV) of exosomes remained in the desirable range post honokiol encapsulation. Exosome-encapsulated honokiol exhibited significantly higher therapeutic efficacy over the free honokiol in WST-1 growth and long-term clonogenicity assays. Flow cytometry-based cell cycle and live/dead cell assay, respectively, confirmed the enhanced effect of exosomal honokiol formulation on cell cycle arrest and apoptosis induction. More significant alterations in the expression of cell cycle- and survival-associated proteins were also observed in cancer cells treated with exosomal honokiol over free honokiol. Higher intracellular accumulation of honokiol was recorded in cancer cells treated with equivalent doses of honokiol as compared to the free honokiol. Together, our work is the first demonstration of exosomal encapsulation of honokiol and its improved antitumor efficacy resulting from improved cellular uptake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.0c03136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495913PMC
September 2020

Assessment of GO/ZnO nanocomposite for solar-assisted photocatalytic degradation of industrial dye and textile effluent.

Environ Sci Pollut Res Int 2020 Sep 6;27(25):32076-32087. Epub 2020 Jun 6.

Amity Institute of Nanotechnology, Amity University, Sector 125, Noida, 201313, India.

An ecofriendly and solar light-responsive graphene oxide wrapped zinc oxide nanohybrid has been synthesized hydrothermally using lemon and honey respectively as chelating and complexing agents. By tuning the reaction conditions, a heterostructure between GO and ZnO has been formed during synthesis. The photocatalytic activity of the synthesized nanohybrid was investigated by degradation of hazardous organic textile dye (methylene blue) as well as wastewater under natural solar light. The nanohybrid exhibited excellent photocatalytic activity towards degradation (~ 89%) of methylene blue (MeB). Furthermore, along with decolorization, 71% of mineralization was also achieved. Interestingly, the nanohybrid has been found to be reusable up to 4 cycles without significant loss of photocatalytic activity. Along with this, the physicochemical parameters of the wastewater generated from textile industry have been also monitored before and after exposure to nanohybrid. The results revealed significant reduction in chemical oxygen demand (COD) (96.33%), biochemical oxygen demand (BOD) (96.23%), and total dissolved solids (TDS) (20.85%), suggesting its potential applicability in textile wastewater treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11356-020-08849-3DOI Listing
September 2020

Modulation of the tumor microenvironment by natural agents: implications for cancer prevention and therapy.

Semin Cancer Biol 2020 May 26. Epub 2020 May 26.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA. Electronic address:

The development of cancer is not just the growth and proliferation of a single transformed cell, but its surrounding environment also coevolves with it. Indeed, successful cancer progression depends on the ability of the tumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells. The interactions between the tumor and stromal cells are bidirectional and mediated through a variety of growth factors, cytokines, metabolites, and other biomolecules secreted by these cells. Tumor-stromal crosstalk creates optimal conditions for the tumor growth, metastasis, evasion of immune surveillance, and therapy resistance, and its targeting is being explored for clinical management of cancer. Natural agents from plants and marine life have been at the forefront of traditional medicine. Numerous epidemiological studies have reported the health benefits imparted on the consumption of certain fruits, vegetables, and their derived products. Indeed, a significant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their derivatives. In this review, we describe fundamental cellular and non-cellular components of the tumor microenvironment and discuss the significance of natural compounds in their targeting. Existing literature provides hope that novel prevention and therapeutic approaches will emerge from ongoing scientific efforts leading to the reduced tumor burden and improve clinical outcomes in cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688484PMC
May 2020

Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer.

J Biol Chem 2020 06 1;295(25):8413-8424. Epub 2020 May 1.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama

Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C--C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.RA119.011748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307206PMC
June 2020

Proteomic Analysis of MYB-Regulated Secretome Identifies Functional Pathways and Biomarkers: Potential Pathobiological and Clinical Implications.

J Proteome Res 2020 02 27;19(2):794-804. Epub 2020 Jan 27.

Department of Pathology, College of Medicine , University of South Alabama , Mobile , Alabama 36617 , United States.

Earlier we have shown important roles of MYB in pancreatic tumor pathobiology. To better understand the role of MYB in the tumor microenvironment and identify MYB-associated secreted biomarker proteins, we conducted mass spectrometry analysis of the secretome from MYB-modulated and control pancreatic cancer cell lines. We also performed in silico analyses to determine MYB-associated biofunctions, gene networks, and altered biological pathways. Our data demonstrated significant modulation ( < 0.05) of 337 secreted proteins in MYB-silenced MiaPaCa cells, whereas 282 proteins were differentially present in MYB-overexpressing BxPC3 cells, compared to their respective control cells. Alteration of several phenotypes such as cellular movement, cell death and survival, inflammatory response, protein synthesis, etc. was associated with MYB-induced differentially expressed proteins (DEPs) in secretomes. DEPs from MYB-silenced MiaPaCa PC cells were suggestive of the downregulation of genes primarily associated with glucose metabolism, PI3K/AKT signaling, and oxidative stress response, among others. DEPs from MYB-overexpressing BxPC3 cells suggested the enhanced release of proteins associated with glucose metabolism and cellular motility. We also observed that MYB positively regulated the expression of four proteins with potential biomarker properties, i.e., FLNB, ENO1, ITGB1, and INHBA. Mining of publicly available databases using Oncomine and UALCAN demonstrated that these genes are overexpressed in pancreatic tumors and associated with reduced patient survival. Altogether, these data provide novel avenues for future investigations on diverse biological functions of MYB, specifically in the tumor microenvironment, and could also be exploited for biomarker development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jproteome.9b00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700759PMC
February 2020

Dysregulation of metabolic enzymes in tumor and stromal cells: Role in oncogenesis and therapeutic opportunities.

Cancer Lett 2020 03 7;473:176-185. Epub 2020 Jan 7.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA. Electronic address:

Altered cellular metabolism is a hallmark of cancer. Metabolic rewiring in cancer cells occurs due to the activation of oncogenes, inactivation of tumor suppressor genes, and/or other adaptive changes in cell signaling pathways. Furthermore, altered metabolism is also reported in tumor-corrupted stromal cells as a result of their interaction with cancer cells or due to their adaptation in the dynamic tumor microenvironment. Metabolic alterations are associated with dysregulation of metabolic enzymes and tumor-stromal metabolic crosstalk is vital for the progressive malignant journey of the tumor cells. Therefore, several therapies targeting metabolic enzymes have been evaluated and/or are being investigated in preclinical and clinical studies. In this review, we discuss some important metabolic enzymes that are altered in tumor and/or stromal cells, and focus on their role in supporting tumor growth. Moreover, we also discuss studies carried out in various cancers to target these metabolic abnormalities for therapeutic exploitation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2020.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067140PMC
March 2020

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope.

Cancers (Basel) 2019 Dec 23;12(1). Epub 2019 Dec 23.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL 36617, USA.

Prostate cancer is the mostly commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death affecting men in the United States. Moreover, it disproportionately affects the men of African origin, who exhibit significantly greater incidence and mortality as compared to the men of European origin. Since androgens play an important role in the growth of normal prostate and prostate tumors, targeting of androgen signaling has remained a mainstay for the treatment of aggressive prostate cancer. Over the years, multiple approaches have been evaluated to effectively target the androgen signaling pathway that include direct targeting of the androgens, androgen receptor (AR), AR co-regulators or other alternate mechanisms that impact the outcome of androgen signaling. Several of these approaches are currently in clinical practice, while some are still pending further development and clinical evaluation. This remarkable progress has resulted from extensive laboratory, pre-clinical and clinical efforts, and mechanistic learnings from the therapeutic success and failures. In this review, we describe the importance of androgen signaling in prostate cancer biology and advances made over the years to effectively target this signaling pathway. We also discuss emerging data on the resistance pathways associated with the failure of various androgen signaling- targeted therapies and potential of this knowledge for translation into future therapies for prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12010051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016833PMC
December 2019

Inflammation, immunosuppressive microenvironment and breast cancer: opportunities for cancer prevention and therapy.

Ann Transl Med 2019 Oct;7(20):593

Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.

Breast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related death in women worldwide. It also exhibits pronounced racial disparities in terms of incidence and clinical outcomes. There has been a growing interest in research community to better understand the role of the microenvironment in cancer. Several lines of evidence have highlighted the significance of chronic inflammation at the local and/or systemic level in breast tumor pathobiology. Inflammation can influence breast cancer progression, metastasis and therapeutic outcome by establishing a tumor supportive immune microenvironment. These processes are mediated through a variety of cytokines and hormones that exert their biological actions either locally or distantly via systemic circulation. Targeting of immune and inflammatory pathways has met tremendous success in some cancers underscoring the importance of research to further our understanding of these systems in breast cancer. This knowledge can be helpful not only in the development of novel prevention and therapeutic strategies, but also help in better prediction of therapeutic responses in patients. This review summarizes some of the significant findings on the role of inflammation in breast cancer to gain collective molecular and mechanistic insights. We also discuss ongoing efforts and future outlook to exploit the existing knowledge for improved breast cancer management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm.2019.09.68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861749PMC
October 2019

Looking at cancer health disparities without the colored lenses.

Cancer Health Disparities 2019 19;3:e1-e9. Epub 2019 Aug 19.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.

Cancer health disparities (CHDs), defined as the adverse differences in cancer incidence and mortality, are prevalent in certain racial and ethnic groups. Underlying causes of CHDs are multi-factorial and debatable. While low socioeconomic status, geographical location, lifestyle and behavioral factors are mostly believed to contribute to CHDs, regardless of ethnic and racial background, significant data now also exist to support a genetic basis of such disparities as well. Clearly, CHDs could best be understood by studying the interplay of multiple (genetic and non-genetic) factors and then translating the resulting knowledge into effective approaches for reducing the existing disparity gaps. This review article highlights these aspects in brief and calls the people of different expertise to work together to make an impact and tackle the challenges associated with CHDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.9777/chd.2019.1004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705599PMC
August 2019

Comparative analysis of exosome isolation methods using culture supernatant for optimum yield, purity and downstream applications.

Sci Rep 2019 03 29;9(1):5335. Epub 2019 Mar 29.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.

Exosomes have received significant attention for their role in pathobiological processes and are being explored as a tool for disease diagnosis and management. Consequently, various isolation methods based on different principles have been developed for exosome isolation. Here we compared the efficacy of four kits from Invitrogen, 101Bio, Wako and iZON along with conventional ultracentrifugation-based method for exosome yield, purity and quality. Cell culture supernatant was used as an abundant source of exosomes, and exosome quantity, size-distribution, zeta-potential, marker-expression and RNA/protein quality were determined. The Invitrogen kit gave the highest yield but the preparation showed broader size-distribution likely due to microvesicle co-precipitation and had the least dispersion stability. Other preparations showed <150 nm size range and good stability. Preparation from iZON column; however, had a broader size-distribution in the lower size range suggestive of some impurities of non-vesicular aggregates. RNA quality from all preparations was comparable; however, proteins from Invitrogen method-based exosomal preparation showed polyethylene glycol (PEG) contamination in mass spectrometry. Chemical impurities from the precipitant could also be the cause of toxicity of Invitrogen method-based exosomal preparation in biological growth measurement assay. Together, these findings should serve as a guide to choose and further optimize exosome isolation methods for their desired downstream applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-41800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441044PMC
March 2019

Drug-loaded exosomal preparations from different cell types exhibit distinctive loading capability, yield, and antitumor efficacies: a comparative analysis.

Int J Nanomedicine 2019 11;14:531-541. Epub 2019 Jan 11.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA,

Background: Despite tremendous advancement, cancer still remains one of the leading causes of death worldwide. Inefficiency of current drug delivery regimens is one important factor that limits the therapeutic efficacy of existing drugs, thus contributing to cancer mortality. To address this limitation, synthetic nanotechnology-based delivery systems have been developed; however, they raise concern of inducing adverse immunogenic reactions. Exosomes (Exos) are nonimmunogenic nanosized vesicles that have received significant attention as efficient drug delivery system.

Methods: Drug loading in Exos were achieved by incubating different cell types viz pancreatic cancer cells (PCCs), pancreatic stellate cells (PSCs), and macrophages (MØs) with Doxorubicin (DOX). Differential ultracentrifugation was performed to isolate exosome and their size was determined by dynamic light scattering analysis. The efficacy of drug packaging into Exos was evaluated by HPLC. Flow cytometry was performed to examine the apoptosis. Cell viability was determined using the WST-1 assay.

Results: PCCs shed the most Exos and were the most efficient in drug loading followed by MØs and PSCs as examined by HPLC quantification. However, when compared for antitumor efficacy, MØ-derived Exos loaded with DOX (MØ-Exo-DOX) showed highest activity followed by PSCs and PCCs.

Conclusion: These varying antitumor activities likely resulted from nondrug contents of Exos since we did not observe any significant differences in their uptake by the cancer cells. Altogether, our data suggest that donor cell-specific differences exist in Exos, which could influence their utility as drug carrier for therapeutic purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S191313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333392PMC
February 2019

Gemcitabine treatment promotes immunosuppressive microenvironment in pancreatic tumors by supporting the infiltration, growth, and polarization of macrophages.

Sci Rep 2018 08 10;8(1):12000. Epub 2018 Aug 10.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.

Chemotherapy-induced immunosuppression poses an additional challenge to its limited efficacy in pancreatic cancer (PC). Here we investigated the effect of gemcitabine on macrophages, which are the first line of immune-defense mechanisms. We observed an increased presence of macrophages in orthotopic human pancreatic tumor xenografts from mice treated with gemcitabine as compared to those from vehicle only-treated mice. Conditioned media from gemcitabine-treated PC cells (Gem-CM) promoted growth, migration and invasion of RAW264.7 macrophage. In addition, Gem-CM also induced upregulation of M2-polarized macrophage markers, arginase-1 and TGF-β1. Cytokine profiling of gemcitabine-treated PC cells identified IL-8 as the most differentially-expressed cytokine. Incubation of Gem-CM with IL-8 neutralizing antibody diminished its ability to induce growth, migration and invasion of RAW264.7 macrophages, but did not abrogate their M2 polarization. Together, our findings identify IL-8 as an important mediator in the gemcitabine-induced infiltration of macrophages within the pancreatic tumor microenvironment and suggest the requirement of additional mechanism(s) for macrophage polarization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-30437-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086900PMC
August 2018

Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells.

Nutr Cancer 2017 Aug-Sep;69(6):932-942. Epub 2017 Jul 18.

a Department of Oncologic Sciences , Mitchell Cancer Institute, University of South Alabama , Mobile , Alabama , USA.

Scope: Hydroxytyrosol (HT), a polyphenol from olives, is a potential anticancer agent. This study was designed to evaluate the anticancer activity of HT against prostate cancer cells, and the mechanism thereof.

Methods And Results: Treatment of LNCaP and C4-2 prostate cancer cells with HT resulted in a dose-dependent inhibition of proliferation. This was in contrast to HT's ineffectiveness against normal prostate epithelial cells RWPE1 and PWLE2, suggesting cancer-cell-specific effect. HT induced G1/S cell cycle arrest, with inhibition of cyclins D1/E and cdk2/4 and induction of inhibitory p21/p27. HT also induced apoptosis, as confirmed by flow cytometry, caspase activation, PARP cleavage, and BAX/Bcl-2 ratio. It inhibited the phosphorylation of Akt/STAT3, and induced cytoplasmic retention of NF-κB, which may explain its observed effects. Finally, HT inhibited androgen receptor (AR) expression and the secretion of AR-responsive prostate-specific antigen.

Conclusion: Castration-resistant prostate cancers retain AR signaling and are often marked by activated Akt, NF-κB, and STAT3 signaling. Our results establish a pleiotropic activity of HT against these oncogenic signaling pathways. Combined with its nontoxic effects against normal cells, our results support further testing of HT for prostate cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01635581.2017.1339818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125781PMC
July 2018

Glucose Metabolism Reprogrammed by Overexpression of IKKε Promotes Pancreatic Tumor Growth.

Cancer Res 2016 12 20;76(24):7254-7264. Epub 2016 Oct 20.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.

Aberrant expression of the kinase IKKε in pancreatic ductal adenocarcinoma (PDAC) has been associated with poor prognosis. In this study, we define a pathobiologic function for IKKε in reprogramming glucose metabolism and driving progression in PDAC. Silencing IKKε in PDAC cells, which overexpressed it endogenously, was sufficient to reduce malignant cell growth, clonogenic potential, glucose consumption, lactate secretion, and expression of genes involved in glucose metabolism, without impacting the basal oxygen consumption rate. IKKε silencing also attenuated c-Myc in a manner associated with diminished signaling through an AKT/GSK3β/c-MYC phosphorylation cascade that promoted MYC nuclear accumulation. In an orthotopic mouse model, IKKε-silenced PDAC exhibited a relative reduction in glucose uptake, tumorigenicity, and metastasis. Overall, our findings offer a preclinical mechanistic rationale to target IKKε to improve the therapeutic management of PDAC in patients. Cancer Res; 76(24); 7254-64. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-16-1666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161695PMC
December 2016

Insights into the Role of microRNAs in Pancreatic Cancer Pathogenesis: Potential for Diagnosis, Prognosis, and Therapy.

Adv Exp Med Biol 2015 ;889:71-87

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36604-1405, USA.

Pancreatic cancer is a highly lethal malignancy and a fourth leading cause of cancer-related death in the United States. Poor survival of pancreatic cancer patients is largely because of its asymptomatic progression to advanced stage against which no effective therapy is currently available. Over the years, we have developed significant knowledge of molecular progression of pancreatic cancer and identified several genetic and epigenetic aberrations to be involved in its etiology and aggressive behavior. In that regard, recent lines of evidence have suggested important roles of microRNAs (miRNAs/miRs) in pancreatic cancer pathogenesis. microRNAs belonging to a family of small, noncoding RNAs are able to control diverse biological processes due to their ability to regulate gene expression at the posttranscriptional level. Accordingly, dysregulation of miRNAs can lead to several disease conditions, including cancer. There is a long list of microRNAs that exhibit aberrant expression in pancreatic cancer and serve as key microplayers in its initiation, progression, metastasis, and chemoresistance. These findings have suggested that microRNAs could be exploited as novel biomarkers for diagnostic and prognostic assessments of pancreatic cancer and as targets for therapy. This book chapter describes clinical problems associated with pancreatic cancer, roles that microRNAs play in various aspects of pancreatic cancer pathogenesis, and envision opportunities for potential use of microRNAs in pancreatic cancer management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-319-23730-5_5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706654PMC
April 2016

Non-synonymous single nucleotide polymorphisms in genes for immunoregulatory galectins: association of galectin-8 (F19Y) occurrence with autoimmune diseases in a Caucasian population.

Biochim Biophys Acta 2012 Oct 7;1820(10):1512-8. Epub 2012 Jun 7.

Center for Molecular Neurology, Department of Neurology, Semmelweis University, Budapest, Hungary.

Background: Galectins are potent immune regulators, with galectin-8 acting as a pro-apoptotic effector on synovial fluid cells and thymocytes and stimulator on T-cells. To set a proof-of-principle example for risk assessment in autoimmunity, and for a mutation affecting physiological galectin sensor functions, a polymorphism in the coding region of the galectin-8 gene (rs2737713; F19Y) was studied for its association with two autoimmune disorders, i.e. rheumatoid arthritis and myasthenia gravis.

Methods: A case-control analysis and a related quantitative trait-association study were performed to investigate the association of this polymorphism in patients (myasthenia gravis 149, rheumatoid arthritis 214 and 134 as primary and repetitive cohorts, respectively) and 365 ethnically matched (Caucasian) healthy controls. Distribution was also investigated in patients grouped according to their antibody status and age at disease onset. Comparative testing for lectin activity was carried out in ELISA/ELLA-based binding tests with both wild-type and F19Y mutant galectin-8 from peripheral blood mononuclear cell lysates of healthy individuals with different genotypes as well as with recombinant wild-type and F19Y mutant galectin-8 proteins.

Results: A strong association was found for rheumatoid arthritis, and a mild one with myasthenia gravis. Furthermore, the presence of the sequence deviation also correlated with age at disease onset in the case of rheumatoid arthritis. The F19Y substitution did not appear to affect carbohydrate binding in solid-phase assays markedly.

General Significance: This is the first report of an association between a galectin-based polymorphism leading to a mutant protein and autoimmune diseases, with evidence for antagonistic pleiotropy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagen.2012.05.015DOI Listing
October 2012
-->