Downregulation of BCL2 by miRNAs augments drug-induced apoptosis--a combined computational and experimental approach.
نویسندگان
چکیده
A number of anti-cancer strategies aim to target the mitochondrial apoptotic machinery to induce tumour cell death. Mitochondria play a key role as death amplifiers by releasing apoptogenic factors from the mitochondrial inter-membrane space into the cytosol. BCL2 proteins are known for their ability to regulate both mitochondrial physiology and cell death, and their deregulated expression often renders cancer cells insensitive to apoptosis-inducing anticancer drugs. Recently, a few microRNAs, a novel class of gene regulators, have been demonstrated to regulate expression of some members of the BCL2 family. Here, we have combined computational and experimental approaches to identify miRNAs that can regulate the anti-apoptotic protein BCL2. We report that miR-195, miR-24-2 and miR-365-2 act as negative regulators of BCL2 through direct binding to their respective binding sites in the 3'-UTR of the human BCL2 gene. Ectopic expression of miR-195, miR-24-2 and miR-365-2 individually led to a significant reduction of the levels of BCL2 protein. Additionally, we found that overexpression of these miRNAs induced dissipation of the mitochondrial membrane potential and release of cytochrome c from mitochondria into the cytosol. Furthermore, we demonstrated that overexpression of these miRNAs not only caused an increase in apoptosis but also augmented the apoptotic effect of etoposide in breast cancer MCF7 cells. These data not only show the apoptotic nature of miR-195, miR-24-2 and miR-365-2 but also highlight the therapeutic potential of these miRNAs.
منابع مشابه
Downregulation of BCL2 by miRNAs augments drug induced apoptosis: Combined computational and experimental approach
متن کامل
Apoptosis induction and proliferation inhibition by silibinin encapsulated in nanoparticles in MIA PaCa-2 cancer cells and deregulation of some miRNAs
Objective(s): Silibinin, as an herbal compound, has anti-cancer activity. Because of low solubility of silibinin in water and body fluids, it was encapsulated in polymersome nanoparticles and its effects were evaluated on pancreatic cancer cells and cancer stem cells.Materials and Methods: MIA PaCa-2 pancreatic cancer cells were treated ...
متن کاملMorphine-induced apoptosis in PC12 cells: role of Bax and Bcl2
Introduction: It was reported that morphine could induce apoptosis in neurons. However, its specific mechanistic pathways remain elusive. The present study was undertaken to determine whether morphine could induce apoptosis in PC12 cells, a neuronal cell line, and the involvement of Bax and Bcl-2, as upstream factors of mitochondrial pathway. Methods: In an experimental study, the viabili...
متن کاملبررسی تاثیر مهار mir-150 بر بیان زنجیره آلفای هموگلوبین در رده سلولیK562.
Background and Aim: MicroRNAs (miRNA) are small noncoding RNA molecules that transcribed by RNA polymerase II. After biogenesis, these molecules act by incorporation into the RNA-induced silencing complex (RISC). MiRNAs are involved in multiple physiological and pathological processes such as proliferation, differentiation, apoptosis and cancer. Recently several studies reported down regulation...
متن کاملThe Study of Petoxifylline Drug Effects on Renal Apoptosis and Bcl2 Gene Expression Changes Following Ischemic Reperfusion Injury in Rat
Background & Target: Ischemia Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. In this study, the effect of pentoxyfylline on bcl2 gene expression changes and cell injury in kidney of rat following Ischemia Reperfusion were evaluated.Methods: In this experimental study, 20 male wistar rats with average weight of...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of cell science
دوره 125 Pt 6 شماره
صفحات -
تاریخ انتشار 2012