Publications by authors named "Yunus Akkoc"

16 Publications

  • Page 1 of 1

Autophagy and Cancer Dormancy.

Front Oncol 2021 19;11:627023. Epub 2021 Mar 19.

Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.

Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called "dormancy" for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.
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http://dx.doi.org/10.3389/fonc.2021.627023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017298PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Treatment of breast cancer with autophagy inhibitory microRNAs carried by AGO2-conjugated nanoparticles.

J Nanobiotechnology 2020 Apr 28;18(1):65. Epub 2020 Apr 28.

Sabanci University Nanotechnology Research and Application Center (SUNUM), Department of Biotechnology, Tuzla, 34956, Istanbul, Turkey.

Nanoparticle based gene delivery systems holds great promise. Superparamagnetic iron oxide nanoparticles (SPIONs) are being heavily investigated due to good biocompatibility and added diagnostic potential, rendering such nanoparticles theranostic. Yet, commonly used cationic coatings for efficient delivery of such anionic cargos, results in significant toxicity limiting translation of the technology to the clinic. Here, we describe a highly biocompatible, small and non-cationic SPION-based theranostic nanoparticles as novel gene therapy agents. We propose for the first-time, the usage of the microRNA machinery RISC complex component Argonaute 2 (AGO2) protein as a microRNA stabilizing agent and a delivery vehicle. In this study, AGO2 protein-conjugated, anti-HER2 antibody-linked and fluorophore-tagged SPION nanoparticles were developed (SP-AH nanoparticles) and used as a carrier for an autophagy inhibitory microRNA, MIR376B. These functionalized nanoparticles selectively delivered an effective amount of the microRNA into HER2-positive breast cancer cell lines in vitro and in a xenograft nude mice model of breast cancer in vivo, and successfully blocked autophagy. Furthermore, combination of the chemotherapy agent cisplatin with MIR376B-loaded SP-AH nanoparticles increased the efficacy of the anti-cancer treatment both in vitro in cells and in vivo in the nude mice. Therefore, we propose that AGO2 protein conjugated SPIONs are a new class of theranostic nanoparticles and can be efficiently used as innovative, non-cationic, non-toxic gene therapy tools for targeted therapy of cancer.
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http://dx.doi.org/10.1186/s12951-020-00615-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189576PMC
April 2020

MicroRNAs as major regulators of the autophagy pathway.

Biochim Biophys Acta Mol Cell Res 2020 05 27;1867(5):118662. Epub 2020 Jan 27.

Sabanci University, Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Orhanli-Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center, Sabanci University, Istanbul 34956, Turkey. Electronic address:

Autophagy is a cellular stress response mechanism activation of which leads to degradation of cellular components, including proteins as well as damaged organelles in lysosomes. Defects in autophagy mechanisms were associated with several pathologies (e.g. cancer, neurodegenerative diseases, and rare genetic diseases). Therefore, autophagy regulation is under strict control. Transcriptional and post-translational mechanisms that control autophagy in cells and organisms studied in detail. Recent studies introduced non-coding small RNAs, and especially microRNAs (miRNAs) in the post-translational orchestration of the autophagic activity. In this review article, we analyzed in detail the current status of autophagy-miRNA connections. Comprehensive documentation of miRNAs that were directly involved in autophagy regulation resulted in the emergence of common themes and concepts governing these complex and intricate interactions. Hence, a better and systematic understanding of these interactions reveals a central role for miRNAs in the regulation of autophagy.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118662DOI Listing
May 2020

Bypassing pro-survival and resistance mechanisms of autophagy in EGFR-positive lung cancer cells by targeted delivery of 5FU using theranostic AgS quantum dots.

J Mater Chem B 2019 12 7;7(46):7363-7376. Epub 2019 Nov 7.

Koc University, Department of Chemistry, 34450 Istanbul, Turkey. and Koc University, Graduate School of Materials Science and Engineering, Rumelifeneri Yolu, Sariyer, 34450 Istanbul, Turkey and KUYTAM, Koc University Surface Science and Technology Center, 34450 Istanbul, Turkey.

Targeted drug delivery systems that combine imaging and therapeutic functions in a single structure have become very popular in nanomedicine. Near-infrared (NIR) emitting AgS quantum dots (QDs) are excellent candidates for this task. Here, we have developed PEGylated AgS QDs functionalized with Cetuximab (Cet) antibody and loaded with an anticancer drug, 5-fluorouracil (5FU). These theranostic QDs were used for targeted NIR imaging and treatment of lung cancer using low (H1299) and high (A549) Epidermal Growth Factor Receptor (EGFR) overexpressing cell lines. The Cet conjugated QDs effectively and selectively delivered 5FU to A549 cells and provided significantly enhanced cell death associated with apoptosis. Interestingly, while treatment of cells with free 5FU activated autophagy, a cellular mechanism conferring resistance to cell death, these EGFR targeting multimodal QDs significantly overcame drug resistance compared to 5FU treatment alone. The improved therapeutic outcome of 5FU delivered to A549 cells by Cet conjugated AgS QDs is suggested as the synergistic outcome of enhanced receptor mediated uptake of nanoparticles, and hence the drug, coupled with suppressed autophagy even in the absence of addition of an autophagy suppressor.
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http://dx.doi.org/10.1039/c9tb01602cDOI Listing
December 2019

Autophagy as a molecular target for cancer treatment.

Eur J Pharm Sci 2019 Jun 11;134:116-137. Epub 2019 Apr 11.

Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul 34956, Turkey. Electronic address:

Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.
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http://dx.doi.org/10.1016/j.ejps.2019.04.011DOI Listing
June 2019

Autophagy and liver cancer.

Turk J Gastroenterol 2018 05;29(3):270-282

Department of Molecular Biology, Genetics and Bioengineering, Sabancı University School of Engineering and Natural Sciences, İstanbul, Turkey; Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Sabancı University, İstanbul, Turkey.

Autophagy is a key biological phenomenon conserved from yeast to mammals. Under basal conditions, activation of autophagy leads to the protein degradation as well as damaged organelles for maintaining cellular homeostasis. Deregulation of autophagy has been identified as a key mechanism contributing to the pathogenesis and progression of several liver diseases, including hepatocellular carcinoma (HCC), one of the most common and mortal types of cancer. Currently used treatment strategies in patients with HCC result in variable success rates. Therefore, novel early diagnosis and treatment techniques should be developed. Manipulation of autophagy may improve responses of cancer cell to treatments and provide novel targeted therapy options for HCC. In this review, we summarized how our understanding of autophagy-cell death connection may have an impact on HCC therapy.
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http://dx.doi.org/10.5152/tjg.2018.150318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284658PMC
May 2018

Development of tailored SPION-PNIPAM nanoparticles by ATRP for dually responsive doxorubicin delivery and MR imaging.

J Mater Chem B 2018 Jan 14;6(2):289-300. Epub 2017 Dec 14.

Koc University, Graduate School of Materials Science and Engineering, Rumelifeneri Yolu, Sariyer, Istanbul, Turkey.

Biocompatible, colloidally stable and ultra-small FeO nanoparticles (SPIONs) coated with poly(N-isopropylacrylamide) (PNIPAM) were synthesized via surface-initiated ATRP (atom transfer radical polymerization) to prevent excessive aggregation of magnetic cores and interparticle crosslinking, and to provide control over polymer content. These SPION-PNIPAM nanoparticles (NPs) have a hydrodynamic size between 8 and 60 nm depending on the PNIPAM content, and hence are ultrasmall in size and have an LCST around 38 °C. They had a high drug-loading capacity reaching 9.6 wt% doxorubicin in the final composition. The Dox release studies revealed pH and temperature-dependent release, which was not reported for PNIPAM before. Release of Dox under physiological conditions was below 20%, but around 90% at 42 °C and pH 5. This dually responsive nature is very advantageous to increase the drug efficacy and reduce side-effects, simultaneously. The cytocompatability of the SPION-PNIPAM NPs and the influence of Dox delivery to cells were investigated via in vitro cell viability, apoptosis, DNA-damage and confocal microscopy studies. The NPs were shown to be highly cytocompatible and induce significant cell death due to Dox when loaded with the drug. Besides, it was seen that the polymeric content can be used as an additional factor in tuning the release kinetics. Lastly, these nanoparticles reduced the signal intensity significantly in the T2 mode, acting as a potential SPION-based contrast agent. Overall, here, we demonstrate the design of small, smart theranostic nanoparticles with high drug-loading capacity and pH-dependent temperature-sensitive release characteristics with the ability to generate contrast in MRI.
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http://dx.doi.org/10.1039/c7tb00646bDOI Listing
January 2018

Surface modifications for phase change cooling applications via crenarchaeon Sulfolobus solfataricus P2 bio-coatings.

Sci Rep 2017 12 20;7(1):17891. Epub 2017 Dec 20.

Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.

Due to its high heat removal capability and exploitation of latent heat, boiling is considered to be one of the most effective cooling methods in industry. Surface structure and wettability are two factors imposing boiling phenomena. Here, we propose an effective and facile method for surface enhancement via crenarchaeon Sulfolobus Solfataricus P2 bio-coatings. The positive effects of such surfaces of bio-coatings were assessed, and enhancements in heat transfer and cooling were obtained. Visualization was also performed, and bubble dynamics of generated bubbles and vapor columns from the tested surfaces with bio-coatings are here presented. Superior performance in terms of boiling heat transfer and cooling was reached with the use of crenarchaeon Sulfolobus Solfataricus P2 coated surfaces. Thus, this study clearly demonstrates the potential of futuristic surfaces with bio-coatings to achieve substantial energy saving and efficiency.
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http://dx.doi.org/10.1038/s41598-017-18192-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738355PMC
December 2017

Autophagy-Regulating microRNAs and Cancer.

Front Oncol 2017 18;7:65. Epub 2017 Apr 18.

Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.

Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis. Consequently, abnormalities of autophagy are associated with a number of diseases, including Alzheimers's disease, Parkinson's disease, and cancer. According to the current view, autophagy seems to serve as a tumor suppressor in the early phases of cancer formation, yet in later phases, autophagy may support and/or facilitate tumor growth, spread, and contribute to treatment resistance. Therefore, autophagy is considered as a stage-dependent dual player in cancer. microRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level. miRNAs control several fundamental biological processes, and autophagy is no exception. Furthermore, accumulating data in the literature indicate that dysregulation of miRNA expression contribute to the mechanisms of cancer formation, invasion, metastasis, and affect responses to chemotherapy or radiotherapy. Therefore, considering the importance of autophagy for cancer biology, study of autophagy-regulating miRNA in cancer will allow a better understanding of malignancies and lead to the development of novel disease markers and therapeutic strategies. The potential to provide study of some of these cancer-related miRNAs were also implicated in autophagy regulation. In this review, we will focus on autophagy, miRNA, and cancer connection, and discuss its implications for cancer biology and cancer treatment.
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http://dx.doi.org/10.3389/fonc.2017.00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394422PMC
April 2017

IBMPFD Disease-Causing Mutant VCP/p97 Proteins Are Targets of Autophagic-Lysosomal Degradation.

PLoS One 2016 21;11(10):e0164864. Epub 2016 Oct 21.

Sabanci University, Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Istanbul, 34956, Turkey.

The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone. We showed that, unlike commonly studied R155C or R191Q mutants, the P137L mutant protein stimulated both autophagosome and autolysosome formation. Moreover, P137L mutant protein itself was a substrate of autophagy. Starvation- and mTOR inhibition-induced autophagy led to the degradation of the P137L mutant protein, while preserving the wild-type and functional VCP/p97. Strikingly, similar to the P137L mutant, other IBMPFD-related VCP/p97 mutants, namely R93C and G157R mutants induced autophagosome and autolysosome formation; and G157R mutant formed aggregates that could be cleared by autophagy. Therefore, cellular phenotypes caused by P137L mutant expression were not isolated observations, and some other IBMPFD disease-related VCP/p97 mutations could lead to similar outcomes. Our results indicate that cellular mechanisms leading to IBMPFD disease may be various, and underline the importance of studying different disease-associated mutations in order to better understand human pathologies and tailor mutation-specific treatment strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164864PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074563PMC
June 2017

MIR376 family and cancer.

Histol Histopathol 2016 Aug 4;31(8):841-55. Epub 2016 Mar 4.

Faculty of Engineering and Natural Sciences, Molecular Biology Genetics and Bioengineering Program, Sabanci University, Orhanli-Tuzla, Istanbul, Turkey.

MicroRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at the post-transcriptional level. They have been implicated in several fundamental biological processes including development, differentiation, apoptosis and stem cell maintenance. There is increasing evidence that microRNAs also play roles in cellular transformation and carcinogenesis by acting either as tumor suppressors or oncogenes. Recent studies introduced MIR376 as an important microRNA family for cancer formation and progression. The MIR376 family is located on human chromosome 14 and it has several members containing identical or similar seed sequences. Biological roles of family members were studied in different cancer settings, including gliomas, leukemia, breast and ovarian cancers. Furthermore, two MIR376 family members, namely MIR376A and MIR376B were implicated in the regulation of macroautophagy (autophagy herein). Since autophagy dysregulation underlies various diseases including cancer, it is essential to understand the role of the MIR376 family in this context. In this article, we summarize the miRNA-cancer connection, and review accumulating data about the involvement of the MIR376 family in cancer biology.
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http://dx.doi.org/10.14670/HH-11-752DOI Listing
August 2016

The inhibition of PI3K and NFκB promoted curcumin-induced cell cycle arrest at G2/M via altering polyamine metabolism in Bcl-2 overexpressing MCF-7 breast cancer cells.

Biomed Pharmacother 2016 Feb 29;77:150-60. Epub 2015 Dec 29.

Istanbul Kultur University, Dept. of Molecular Biology and Genetics, Atakoy Campus, 34156 Istanbul, Turkey.

Bcl-2 protein has been contributed with number of genes which are involved in oncogenesis. Among the many targets of Bcl-2, NFκB have potential role in induction of cell cycle arrest. Curcumin has potential therapeutic effects against breast cancer through multiple signaling pathways. In this study, we investigated the role of curcumin in induction of cell cycle arrest via regulating of NFκB and polyamine biosynthesis in wt and Bcl-2+ MCF-7 cells. To examine the effect of curcumin on cell cycle regulatory proteins, PI3K/Akt, NFκB pathways and polyamine catabolism, we performed immunoblotting assay. In addition, cell cycle analysis was performed by flow cytometry. The results indicated that curcumin induced cell cycle arrest at G2/M phase by downregulation of cyclin B1 and Cdc2 and inhibited colony formation in MCF-7wt cells. However, Bcl-2 overexpression prevented the inhibition of cell cycle associated proteins after curcumin treatment. The combination of LY294002, PI3K inhibitor, and curcumin induced cell cycle arrest by decreasing CDK4, CDK2 and cyclin E2 in Bcl-2+ MCF-7 cells. Moreover, LY294002 further inhibited the phosphorylation of Akt in Bcl-2+ MCF-7 cells. Curcumin could suppress the nuclear transport of NFκB through decreasing the interaction of P-IκB-NFκB. The combination of wedelolactone, NFκB inhibitor, and curcumin acted different on SSAT expression in wt MCF-7 and Bcl-2+ MCF-7 cells. NFκB inhibition increased the SSAT after curcumin treatment in Bcl-2 overexpressed MCF-7 cells. Inhibition of NFκB activity as well as suppression of ROS generation with NAC resulted in the partial relief of cells from G2/M checkpoint after curcumin treatment in wt MCF-7 cells. In conclusion, the potential role of curcumin in induction of cell cycle arrest is related with NFκB-regulated polyamine biosynthesis.
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http://dx.doi.org/10.1016/j.biopha.2015.12.007DOI Listing
February 2016

Physiological and pathological significance of the molecular cross-talk between autophagy and apoptosis.

Histol Histopathol 2016 May 18;31(5):479-98. Epub 2015 Dec 18.

Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabanci University, Istanbul, Turkey.

Autophagy and apoptosis are two important molecular mechanisms that maintain cellular homeostasis under stress conditions. Autophagy represents an intracellular mechanism responsible for turnover of organelles and long-lived proteins through a lysosome-dependent degradation pathway. Cell death signals or sustained stress might trigger programmed cell death pathways, and among them, apoptosis is the most extensively studied one. Recent studies indicate the presence of a complex interplay between autophagy and apoptosis. Physiological relevance of autophagy-apoptosis crosstalk was mainly shown in vitro. However, in vivo consequences possibly exist both during health and disease. In this review, we will summarize the current knowledge about molecular mechanisms connecting autophagy and apoptosis, and about the significance of this crosstalk for human health.
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http://dx.doi.org/10.14670/HH-11-714DOI Listing
May 2016

Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl-2 through activation of autophagy in MCF-7 cells.

Biomed Pharmacother 2015 Apr 4;71:161-71. Epub 2015 Mar 4.

Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey.

Curcumin is a natural anti-cancer agent derived from turmeric (Curcuma longa). Curcumin triggers intrinsic apoptotic cell death by activating mitochondrial permeabilization due to the altered expression of pro- and anti-apoptotic Bcl-2 family members. Phosphoinositol-3-kinase (PI3K) and Akt, key molecular players in the survival mechanism, have been shown to be associated with the Bcl-2 signaling cascade; therefore, evaluating the therapeutic efficiency of drugs that target both survival and the apoptosis mechanism has gained importance in cancer therapy. We found that Bcl-2 overexpression is a limiting factor for curcumin-induced apoptosis in highly metastatic MCF-7 breast cancer cells. Forced overexpression of Bcl-2 also blocked curcumin-induced autophagy in MCF-7 cells, through its inhibitory interactions with Beclin-1. Pre-treatment of PI3K inhibitor LY294002 enhanced curcumin-induced cell death, apoptosis, and autophagy via modulating the expression of Bcl-2 family members and autophagosome formation in MCF-7 breast cancer cells. Atg7 silencing further increased apoptotic potential of curcumin in the presence or absence of LY294002 in wt and Bcl-2+ MCF-7 cells. The findings of this study support the hypothesis that blocking the PI3K/Akt pathway may further increased curcumin-induced apoptosis and overcome forced Bcl-2 expression level mediated autophagic responses against curcumin treatment in MCF-7 cells.
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http://dx.doi.org/10.1016/j.biopha.2015.02.029DOI Listing
April 2015

Polyamines modulate the roscovitine-induced cell death switch decision autophagy vs. apoptosis in MCF-7 and MDA-MB-231 breast cancer cells.

Mol Med Rep 2015 Jun 4;11(6):4532-40. Epub 2015 Feb 4.

Department of Molecular Biology and Genetics, İstanbul Kültür University, Atakoy Campus, Istanbul 34156, Turkey.

Current clinical strategies against breast cancer mainly involve the use of anti‑hormonal agents to decrease estrogen production; however, development of resistance is a major problem. The resistance phenotype depends on the modulation of cell‑cycle regulatory proteins, cyclins and cyclin‑dependent kinases. Roscovitine, a selective inhibitor of cyclin‑dependent kinases, shows high therapeutic potential by causing cell‑cycle arrest in various cancer types. Autophagy is a type of cell death characterized by the enzymatic degradation of macromolecules and organelles in double‑ or multi‑membrane autophagic vesicles. This process has important physiological functions, including the degradation of misfolded proteins and organelle turnover. Recently, the switch between autophagy and apoptosis has been proposed to constitute an important regulator of cell death in response to chemotherapeutic drugs. The process is regulated by several proteins, such as the proteins of the Atg family, essential for the initial formation of the autophagosome, and PI3K, important at the early stages of autophagic vesicle formation. Polyamines (PAs) are small aliphatic amines that play major roles in a number of eukaryotic processes, including cell proliferation. The PA levels are regulated by ornithine decarboxylase (ODC), the rate‑limiting enzyme in PA biosynthesis. In this study, we aimed to investigate the role of PAs in roscovitine‑induced autophagic/apoptotic cell death in estrogen receptor‑positive MCF‑7 and estrogen receptor‑negative MDA‑MB‑231 breast cancer cells. We show that MDA‑MB‑231 cells are more resistant to roscovitine than MCF‑7 cells. This difference was related to the regulation of autophagic key molecules in MDA‑MB‑231 cells. In addition, we found that exogenous PAs have a role in the cell death decision between roscovitine‑induced apoptosis or autophagy in MCF‑7 and MDA‑MB‑231 breast cancer cells.
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http://dx.doi.org/10.3892/mmr.2015.3303DOI Listing
June 2015