Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell
ABSTRACT Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.
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- "The majority of relevant preclinical studies using numerous chemotherapeutics including vorinostat, cyclophosphamide, and imatinib have demonstrated that autophagy significantly inhibits the efficacy of several classes of anticancer agents and helps to drive the acquired resistance   . Furthermore, accumulating evidence has indicated that autophagy is involved in adaptation of cancer cells to chemotherapy  . These observations suggest that under chemotherapeutic treatments, autophagy is often activated as a cytoprotective mechanism for tumor cell to survive the effects of anticancer drugs which, in turn, may drive chemoresistance . "
ABSTRACT: Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.Seminars in Cancer Biology 03/2015; ePub ahead of print. DOI:10.1016/j.semcancer.2015.03.001 · 9.33 Impact Factor
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- "For example, miRs-193a-3p and 146a suppress apoptosis via modulation of proapoptotic CASP2L through SRSF2, and SMAD4, respectively, whereas decreased miR- 199a-5p in resistant cells increases cell proliferation by activation of autophagy via ATG7. Importantly, in all three studies, the sensitivity to the respective chemotherapeutics could be altered in vitro by modulating miRNA abundance (Tomokuni et al., 2011; Ma et al., 2012; Xu et al., 2012). Ji et al. (2009) recently dissected the miRNA contribution for the response to adjuvant therapy with IFN␣ thereby confirming the therapeutic potential of miRNA-guided treatment modalities in HCC. "
ABSTRACT: Since their discovery more than a decade ago microRNAs have been demonstrated to have profound effects on almost every aspect of biology. Numerous studies in recent years have shown that microRNAs have important roles in development and in the etiology and progression of disease. This review is focused on microRNAs and the roles they play in liver development, regeneration and liver disease; particularly chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, viral hepatitis and primary liver cancer. The key microRNAs identified in liver development and chronic liver disease will be discussed together with, where possible, the target messenger RNAs that these microRNAs regulate to profoundly alter these processes.The international journal of biochemistry & cell biology 04/2014; 54. DOI:10.1016/j.biocel.2014.04.002 · 4.24 Impact Factor
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- "17. Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ, Xu H et al (2012) Differential regulation of amyloid-beta endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J Biol Chem 287(53):44593–44601. doi:10.1074/jbc.M112.420224 "
ABSTRACT: Macroautophagy (hereafter referred to as autophagy) is an evolutionary conserved degradation pathway that targets cytoplasmic substrates, including long-lived proteins, protein aggregates and damaged organelles, and leads to their degradation in lysosomes. Beyond its role in adaptation to cellular stresses, such as nutrient deprivation, hypoxia and toxins, recent studies attributed a central role to autophagy in aging and life span determination. Moreover, alterations and abnormalities of autophagy may contribute to a number of important health problems, including cancer, myopathies, metabolic disorders and, the focus of this review, aging-related neurodegenerative diseases. Some disease-related, mutant and aggregation-prone proteins may be cleared by autophagy; on the other hand, disregulation of the autophagy pathways may also contribute to neurotoxicity observed in degenerative pathologies. microRNAs (miRNAs) are endogenous regulators of gene expression, and their deregulation was reported in several aging-related conditions. Studies in the last few years introduced miRNAs as novel and potent regulators of autophagy. In this review article, we will summarize the connection between autophagy, aging and Alzheimer’s, Parkinson’s and Huntington’s diseases, and discuss the role of autophagy-related miRNAs in this context.11/2013; 4(October):1-36. DOI:10.1007/s40139-013-0031-x