HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROS–JNK–autophagy pathway

Ni, Zhenhong; Wang, Bin; Dai, Xufang; Ding, Wen; Yang, Ting; Li, Xinzhe; Lewin, Seth J.; Xu, Liang; Lian, Jiqin; He, Fengtian

doi:10.1016/j.freeradbiomed.2014.02.012

Cited by 84 publications

(68 citation statements)

References 57 publications

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“…that salicylate reversed palmitic acid-induced cardiomyocyte dysfunction. Last but not the least, it is noteworthy that possible contribution from other autophagy regulatory machineries such as JNK-mediated phosphorylation of Bcl-2 to disengage the association between Bcl-2 and the autophagy protein Beclin-1 [50] cannot be excluded at this time. Nonetheless, our data indicated unchanged levels of Beclin-1, not favoring involvement of mTOR-independent regulation of autophagy although future study is needed to consolidate possible involvement (or non-involvement) of other autophagy regulatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKβ-AMPK-dependent regulation of autophagy

Liang

Shou

Zhao

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a variety of biological processes including obesity. However, the precise mechanism of action behind obesity-induced changes in autophagy still remains elusive. This study was designed to examine the role of the antioxidant catalase in high fat diet-induced changes in cardiac geometry and function as well as the underlying mechanism of action involved with a focus on autophagy. Wild-type (WT) and transgenic mice with cardiac overexpression of catalase were fed low or high fat diet for 20 weeks prior to assessment of myocardial geometry and function. High fat diet intake triggered obesity, hyperinsulinemia, and hypertriglyceridemia, the effects of which were unaffected by catalase transgene. Myocardial geometry and function were compromised with fat diet intake as manifested by cardiac hypertrophy, enlarged left ventricular end systolic and diastolic diameters, fractional shortening, cardiomyocyte contractile capacity and intracellular Ca²⁺ mishandling, the effects of which were ameliorated by catalase. High fat diet intake promoted reactive oxygen species production and suppressed autophagy in the heart, the effects of which were attenuated by catalase. High fat diet intake dampened phosphorylation of inhibitor kappa B kinase β(IKKβ), AMP-activated protein kinase (AMPK) and tuberous sclerosis 2 (TSC2) while promoting phosphorylation of mTOR, the effects of which were ablated by catalase. In vitro study revealed that palmitic acid compromised cardiomyocyte autophagy and contractile function in a manner reminiscent of fat diet intake, the effect of which was significantly alleviated by inhibition of IKKβ, activation of AMPK and induction of autophagy. Taken together, our data revealed that the antioxidant catalase counteracts against high fat diet-induced cardiac geometric and functional anomalies possibly via an IKKβ-AMPK-dependent restoration of myocardial autophagy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

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Section: Discussionmentioning

confidence: 99%

Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKβ-AMPK-dependent regulation of autophagy

Liang

Shou

Zhao

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Among them, CQ and its derivatives have gained increasing attention due to their favorable pharmacological properties and physiological tolerance as evidenced by their long history of use as anti-malarial agents and in diseases such as rheumatoid arthritis. CQ inhibits lysosomal acidification, which blocks the terminal stage of autophagy and has indeed been shown to potentiate the anticancer effects of various chemotherapeutic drugs both in vitro and in vivo (32)(33)(34)(35). Currently, multiple clinical trials using CQ as a sensitizing reagent, in combination with standard cancer therapies, are under evaluation in different tumor types, including lung cancer, glioblastoma multiforme, multiple myeloma, breast cancer, melanoma, colon cancer, prostate cancer, and advanced solid tumors unresponsive to chemotherapy (http:// clinicaltrials.gov).…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibition enhances sensitivity of endometrial carcinoma cells to paclitaxel

Liu

2015

International Journal of Oncology

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Abstract. Autophagy has been shown to be involved in cancer cell resistance to chemotherapy. Paclitaxel, a widely used chemotherapeutic drug, was demonstrated to induce autophagy in various cancer cells. Therefore, we sought to evaluate the role of autophagy on the paclitaxel-induced cell death in endometrial carcinoma. In this study, we found that paclitaxel induced autophagy in paclitaxel-insensitive HEC-1A and JEC cells, exhibiting an increased microtubule associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, a decrease in p62/ SQSTM1 abundance, the upregulation of Beclin 1 expression and punctate dots of yellow fluorescent protein (YFP)-LC3 in the cytosol. Paclitaxel-mediated cell death was further potentiated by pretreatment with autophagy inhibitor chloroquine (CQ) or shRNA against the autophagic gene beclin 1. Moreover, paclitaxel stimulated reactive oxygen species (ROS) generation, and inhibition of the ROS by antioxidant N-acetyl-cysteine (NAC) blocked paclitaxel-induced autophagy, indicating that paclitaxel-induced autophagy in endometrial carcinoma cells is mediated by ROS. These findings suggest that paclitaxelelicited autophagic response plays a protective role that impedes the eventual death of endometrial carcinoma cell, and that autophagy-inhibitor therapy could be an effective and potent strategy to improve paclitaxel treatment outcomes in the treatment of endometrial carcinoma.

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“…Bcl-2 has been shown to function as a negative regulator of cellular apoptosis (27) and increasing evidence has implicated Bcl-2 in the regulation of autophagy (28,29). Bcl-2 was found to bind to Beclin1 and disrupt autophagy, and overexpression of Bcl-2 in the heart inhibited autophagy in response to starvation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of microRNA-101 attenuates hypoxia/reoxygenation-induced apoptosis through induction of autophagy in H9c2 cardiomyocytes

Jiang

Chen

et al. 2015

Molecular Medicine Reports

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Abstract. Autophagy is a cellular self-catabolic process responsible for the degradation of proteins and organelles. Autophagy is able to promote cell survival in response to stress, and increased autophagy amongst cardiomyocytes has been identified in conditions of heart failure, starvation and ischemia/reperfusion. However, the detailed regulatory mechanisms underlying autophagy in heart disease have remained elusive. MicroRNAs (miRNAs) have been implicated in the regulation of autophagy in cells under stress. In the present study, the protective effect of miRNA (miR)-101 on hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis was investigated. It was revealed that H/R induced apoptosis in H9c2 cardiomyocytes, accompanied by a downregulation of miR-101 expression. Further investigation identified Ras-related protein Rab-5A (RAB5A) as a direct target of miR-101. RAB5A was previously reported to be involved in autophagy; therefore, the present study further focused on the role of miR-101 in the regulation of autophagy under H/R and found that the inhibition of miR-101 attenuated H/R-induced apoptosis, at least partially, via the induction of autophagy. In conclusion, the results of the present study revealed a beneficial effect of miR-101 inhibition on H/R-induced apoptosis in cardiomyocytes, indicating that miR-101 inhibition may present a potential therapeutic agent in the treatment or prevention of heart diseases. IntroductionAutophagy is a cellular self-catabolic process responsible for the degradation of long-lived proteins and organelles. During autophagy, cytoplasmic constituents are sequestered into autophagosomes and degraded via the lysosomal pathway (1).Autophagy is able to promote cell survival in response to stress. However, progressive autophagy also induces cell death (2). Therefore, autophagy not only has a crucial role in the regulation of normal development, but dysregulated or defective autophagy is associated with disease.MicroRNAs (miRNAs) are a group of endogenous, non-coding, single-strand, small RNAs of 22-25 nucleotides, which regulate gene expression at the post-transcriptional level, predominantly through base pairing with the 3'-untranslated region (3'-UTR) of target mRNAs, which results in mRNA degradation or translational repression (3). It has been revealed that miRNAs regulate >30% of genes, which are associated with almost all major cellular processes, including cell proliferation, differentiation, apoptosis and migration, as well as immune responses (4). Myocardial tissue injury induced by ischemia and hypoxia is a major factor underlying the development of fatal diseases. The main cause of myocardial ischemic injury is myocardial cell apoptosis induced by myocardial hypoxia (5). Furthermore, subsequent reoxygenation may further aggravate the damage (6). Multiple miRNAs have been shown to function as protectors against hypoxia/reoxygenation (H/R)-induced myocardial injury (7-9). However, the specific molecular mechanisms underlying this effect have remained elusive.Accumu...

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HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROS–JNK–autophagy pathway

Cited by 84 publications

References 57 publications

Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKβ-AMPK-dependent regulation of autophagy

Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKβ-AMPK-dependent regulation of autophagy

Autophagy inhibition enhances sensitivity of endometrial carcinoma cells to paclitaxel

Inhibition of microRNA-101 attenuates hypoxia/reoxygenation-induced apoptosis through induction of autophagy in H9c2 cardiomyocytes

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