Publications by authors named "Gustavo W Leone"

9 Publications

  • Page 1 of 1

Cyclin D-CDK4/6 functions in cancer.

Adv Cancer Res 2020 2;148:147-169. Epub 2020 Apr 2.

Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.
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http://dx.doi.org/10.1016/bs.acr.2020.02.002DOI Listing
September 2020

Modeling Human Cancer-induced Cachexia.

Cell Rep 2019 08;28(6):1612-1622.e4

Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University, Columbus, OH 43210, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia is associated with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models, which fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology as cachectic patients. We envision that the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.
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http://dx.doi.org/10.1016/j.celrep.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733019PMC
August 2019

Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer.

Breast Cancer Res 2019 07 17;21(1):80. Epub 2019 Jul 17.

The Comprehensive Cancer Center, College of Medicine, The Ohio State University, 460 West 12th Avenue, Columbus, OH, 43210, USA.

Background: A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood.

Methods: We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer.

Results: Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for < 6 months vs ≥ 6 months showed significant enrichment of Notch signaling pathway genes, along with a trend for enrichment for luminal progenitor gene signature similar to what is observed in BRCA1 mutation carriers and basal-like breast tumors.

Conclusions: We report here for the first time that forced or abrupt involution of the mammary glands following pregnancy and lack of breastfeeding results in expansion of luminal progenitor cells, higher inflammation, proliferation, and ductal hyperplasia, a known risk factor for developing breast cancer.
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http://dx.doi.org/10.1186/s13058-019-1163-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637535PMC
July 2019

Periostin/β1integrin interaction regulates p21-activated kinases in valvular interstitial cell survival and in actin cytoskeleton reorganization.

Biochim Biophys Acta Gen Subj 2019 05 10;1863(5):813-829. Epub 2019 Feb 10.

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.. Electronic address:

The matricellular protein periostin (PN) promotes postnatal valve remodeling and maturation. Incomplete remodeling of the valve can trigger degenerative processes that lead to a myxomatous phenotype that includes loss of PN. However, signaling pathways involved that link valvular-interstitial-fibroblast cells (VICs) to proliferation, migration and actin remodeling functions are unclear. The p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements and cell proliferation/adhesion/migration functions in a variety of cellular contexts, including normal cells and cancer cells. This study shows that Pak1, but not Pak2 and Pak4, is a critical mediator of VIC survival and actin organization, and that the molecular signaling regulating actin-remodeling is initiated upon PN/beta-integrin-induced phosphorylation of the focal-adhesion-kinase (Fak) (Y397). Molecular and pharmacological inhibition of key components of PN/Fak/Akt1 signaling abolished the PN-induced actin polymerization and the activation of mTOR, p70S6K and Pak1. Similarly, blocking mTOR inhibited p70S6K, Pak1 phosphorylation and consequently actin-polymerization. Accordingly, inhibiting p70S6K blocked Pak1 phosphorylation and actin polymerization, and subsequently inhibited adhesion and growth of VICs. Periostin-induced Akt1 activation of Pak1 is independent of Cdc42 and Rac1 GTPases, and Akt1 is both downstream and upstream of Pak1. Further, the PN-Pak1-induced Akt1 protects cells from apoptosis through suppression of transcriptional activation of Forkhead-Transcription-Factor (FKHR). In contrast, kinase deficient Pak1 increases apoptosis by increasing FKHR-mediated transcriptional activation. These studies define new functional significance of PN-Fak-Akt1-Pak1 signaling that at least partly regulates Akt1-induced actin polymerization and FKHR-mediated transcriptional activation, which may eventually regulate the mature-valve-leaflet remodeling function, and also FKHR-mediated transcriptional activation for pro-survival of VICs.
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http://dx.doi.org/10.1016/j.bbagen.2018.12.015DOI Listing
May 2019

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development.

J Clin Invest 2017 Oct 11;127(10):3796-3809. Epub 2017 Sep 11.

Department of Cancer Biology and Genetics.

Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.
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http://dx.doi.org/10.1172/JCI91561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617672PMC
October 2017

IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB.

J Immunol 2017 10 25;199(7):2333-2342. Epub 2017 Aug 25.

The James Cancer Hospital and Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;

Group 3 innate lymphoid cells (ILC3s) are important regulators of the immune system, maintaining homeostasis in the presence of commensal bacteria, but activating immune defenses in response to microbial pathogens. ILC3s are a robust source of IL-22, a cytokine critical for stimulating the antimicrobial response. We sought to identify cytokines that can promote proliferation and induce or maintain IL-22 production by ILC3s and determine a molecular mechanism for this process. We identified IL-18 as a cytokine that cooperates with an ILC3 survival factor, IL-15, to induce proliferation of human ILC3s, as well as induce and maintain IL-22 production. To determine a mechanism of action, we examined the NF-κB pathway, which is activated by IL-18 signaling. We found that the NF-κB complex signaling component, p65, binds to the proximal region of the promoter and promotes transcriptional activity. Finally, we observed that CD11c dendritic cells expressing IL-18 are found in close proximity to ILC3s in human tonsils in situ. Therefore, we identify a new mechanism by which human ILC3s proliferate and produce IL-22, and identify NF-κB as a potential therapeutic target to be considered in pathologic states characterized by overproduction of IL-18 and/or IL-22.
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http://dx.doi.org/10.4049/jimmunol.1601554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624342PMC
October 2017

Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis.

Blood 2008 Jan 9;111(2):816-28. Epub 2007 Oct 9.

Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, USA.

Several RNA binding proteins (RBPs) have been implicated in the progression of chronic myelogenous leukemia (CML) from the indolent chronic phase to the aggressively fatal blast crisis. In the latter phase, expression and function of specific RBPs are aberrantly regulated at transcriptional or posttranslational levels by the constitutive kinase activity of the BCR/ABL oncoprotein. As a result, altered expression/function of RBPs leads to increased resistance to apoptotic stimuli, enhanced survival, growth advantage, and differentiation arrest of CD34+ progenitors from patients in CML blast crisis. Here, we identify the mRNAs bound to the hnRNP-A1, hnRNP-E2, hnRNP-K, and La/SSB RBPs in BCR/ABLtransformed myeloid cells. Interestingly, we found that the mRNA encoding the transcription factor E2F3 associates to hnRNP-A1 through a conserved binding site located in the E2F3 3' untranslated region (UTR). E2F3 levels were up-regulated in CML-BCCD34+ in a BCR/ABL kinase- and hnRNP-A1 shuttling-dependent manner. Moreover, by using shRNA-mediated E2F3 knock-down and BCR/ABL-transduced lineage-negative bone marrow cells from E2F3+/+ and E2F3-/- mice, we show that E2F3 expression is important for BCR/ABL clonogenic activity and in vivo leukemogenic potential. Thus, the complexity of the mRNA/RBP network, together with the discovery of E2F3 as an hnRNP-A1-regulated factor, outlines the relevant role played by RBPs in posttranscriptional regulation of CML development and progression.
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http://dx.doi.org/10.1182/blood-2007-05-090472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2200861PMC
January 2008

Bone morphogenetic protein 3B silencing in non-small-cell lung cancer.

Oncogene 2004 Apr;23(20):3521-9

Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.

Bone morphogenetic protein 3B (BMP3B) is a member of the TGF-beta superfamily. The BMP3B promoter sequence was previously identified as a target for aberrant DNA methylation in non-small-cell lung cancer (NSCLC). Aberrant DNA hypermethylation in the BMP3B promoter is associated with downregulation of BMP3B transcription in both primary human lung cancers as well as lung cancer cell lines. In order to understand the mechanisms of BMP3B silencing in lung cancer, a sample set of 91 primary NSCLCs was used to detect aberrant BMP3B promoter methylation, mutations in the coding sequence of BMP3B, and loss of heterozygosity (LOH). Our results showed that 45 of 91 (or 49.5%) tested primary NSCLCs exhibited increased promoter methylation, and 40% demonstrated LOH in at least one of the flanking microsatellite markers sJRH and D10S196 (63 kb upstream or 3.338 Mbp downstream of BMP3B). The lung cancer cell line A549, a type II alveolar epithelial human lung cancer cell line, is characterized by aberrant DNA promoter methylation. We used retroviral vector constructs containing the BMP3B cDNA to re-express the gene in A549 cells and to investigate the effects on cell growth. No change in the cell growth rate was observed after BMP3B re-expression, as compared to the vector controls. Although the number of colonies formed in anchorage-dependent assays was only slightly decreased, the colony-forming ability of A549 cells after BMP3B expression in anchorage-independent assays in soft agar was significantly reduced to 10% (P<0.005, t-test). Moreover, the in vivo tumorigenicity assay in nude mice indicated that cells re-expressing BMP3B grew significantly slower than cells not expressing BMP3B (P<0.05, t-test). In conclusion, this study provides evidence that BMP3B expression is repressed by different mechanisms in lung cancer, and that the silencing of BMP3B promotes lung tumor development.
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http://dx.doi.org/10.1038/sj.onc.1207441DOI Listing
April 2004

Molecular cloning and expression of equine calcitonin, calcitonin gene-related peptide-I, and calcitonin gene-related peptide-II.

Mol Cell Endocrinol 2003 Jan;199(1-2):119-28

Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Road, Columbus 43210, USA.

In this study, we describe the cloning and tissue expression of equine calcitonin (CT), calcitonin-gene related peptide (CGRP)-I, and CGRP-II cDNA. We also describe a novel divergent form of CGRP (CGRP-I). Equine CT has greatest homology (>85%) to human, rat and mouse subgroups of calcitonins. Equine CGRP-I has low homology (<59%) to CGRPs of other species. The signal and N-terminal peptides for equine CT and CGRP-I were identical, indicating that these peptides are encoded by a gene equivalent to the human CALC-I gene. Equine CGRP-II has >80% homology to chicken, human, rat, ovine, swine, and bovine CGRPs. The homology between equine CGRP-I and CGRP-II is low (56%). The high homology of equine CGRP-II and the low homology of equine CGRP-I to CGRP in other species were unexpected findings. Northern blot analysis revealed that CT mRNA expression was restricted to the thyroid gland; however, RT-PCR revealed that CT mRNA expression was also present in the pituitary gland and in the liver. CGRP-I and CGRP-II mRNA expression was present in several regions of the nervous system and other tissues of neuroectodermal origin. An unexpected finding was CGRP-I expression in the kidney by both Northern analysis and by RT-PCR. Based on these results, CT gene expression in the horse was not restricted to the thyroid gland, and CT may be important in regulating pituitary cell function. CGRPs are widely expressed in tissues of the central and peripheral nervous system. Information from this study will be valuable to study the role of CT, CGRP-I, and CGRP-II in equine health and disease.
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http://dx.doi.org/10.1016/s0303-7207(02)00289-7DOI Listing
January 2003