Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells

Choi, Min Jung; Park, Eun Jung; Min, Kyoung Jin; Park, Jong‐Wook; Kwon, Taeg Kyu

doi:10.1016/j.tiv.2011.01.010

Cited by 75 publications

(49 citation statements)

References 29 publications

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“…Reactive oxygen species serve a role in the pro-apoptotic effect of WA in various types of cancer, including leukemia (20) and renal cancer (21). Proteasome inhibition, the induction of endoplasmic reticulum stress, downregulation of Akt serine/threonine kinase phosphorylation and the downregulation of Janus kinase/signal transducer and activator of transcription 3 signaling are also suggested to contribute to cancer cell apoptosis following WA treatment (4,22,23). Transcription factors, including nuclear factor-κB (NF-κB) and mitogen-activated protein kinases, contribute to WA-mediated induction of apoptosis of leukemia (4,24), glioblastoma (25) and breast cancer (26).…”

Section: Discussionmentioning

confidence: 99%

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Kim

Hwang

et al. 2017

Oncology Letters

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Abstract. Human gastric adenocarcinoma (AGS) is one of the most common types of malignant tumor and the third-leading cause of tumor-associated mortality worldwide. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, exhibits antitumor activity in a variety of cancer models. However, to the best of our knowledge, the direct effect of WA on AGS cells has not previously been determined. The present study investigated the effects of WA on the proliferation and metastatic activity of AGS cells. WA exerted a dose-dependent cytotoxic effect on AGS cells. The effect was associated with cell cycle arrest at the G2/M phase and the expression of apoptotic proteins. Additionally, WA treatment resulted in a decrease in the migration and invasion ability of the AGS cells, as demonstrated using a wound healing assay and a Boyden chamber assay. These results indicate that WA directly inhibits the proliferation and metastatic activity of gastric cancer cells, and suggest that WA may be developed as a drug for the treatment of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Kim

Hwang

et al. 2017

Oncology Letters

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“…Similarly, WA promotes ER stress-induced apoptosis in human renal carcinoma cells. 37 Accumulating data indicate that ER stress is a potent trigger of autophagy. [16][17][18] In these cases, ER stress-induced autophagy counterbalances ER expansion, removes aggregated proteins, and has a cytoprotective function.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Feng

Jiang

et al. 2016

Autophagy

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In contrast to normal tissue, cancer cells display profound alterations in protein synthesis and degradation. Therefore, proteins that regulate endoplasmic reticulum (ER) homeostasis are being increasingly recognized as potential therapeutic targets. The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. However, interactions between autophagy, the proteasome, and ER stress pathways in cancer remain largely undefined. This study demonstrated that withaferin-A (WA), the biologically active withanolide extracted from Withania somnifera, significantly increased autophagosomes, but blocked the degradation of autophagic cargo by inhibiting SNARE-mediated fusion of autophagosomes and lysosomes in human pancreatic cancer (PC) cells. WA specifically induced proteasome inhibition and promoted the accumulation of ubiquitinated proteins, which resulted in ER stress-mediated apoptosis. Meanwhile, the impaired autophagy at early stage induced by WA was likely activated in response to ER stress. Importantly, combining WA with a series of ER stress aggravators enhanced apoptosis synergistically. WA was well tolerated in mice, and displayed synergism with ER stress aggravators to inhibit tumor growth in PC xenografts. Taken together, these findings indicate that simultaneous suppression of 2 key intracellular protein degradation systems rendered PC cells vulnerable to ER stress, which may represent an avenue for new therapeutic combinations for this disease.

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“…One potential challenge will be the development of agents that specifically target the cyto-protective functions of the UPR ER while either potentiating or maintaining the pro-apoptotic functions of this response. Promising agents [95, 125–136] are under investigation in various types of cancer, and possible combination therapies utilizing ER stress-inducing agents are encouraging approaches (Table 1). In conclusion, UPR ER -mediated induction of the mitochondrial intrinsic apoptosis pathway in response to anticancer targeting is an attractive strategy for novel cancer therapy investigations and thus offers considerable potential for future drug design for the treatment of various malignancies.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer

Bhat

Chaudhary

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

108

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Abrogation of endoplasmic reticulum (ER) protein folding triggered by exogenous or endogenous factors, stimulates a cellular stress response, termed ER stress. ER stress reestablishes ER homeostasis through integrated signaling termed the ER-unfolded protein response (UPRER). In the presence of severe toxic or prolonged ER stress, the pro-survival function of UPRER is transformed into a lethal signal transmitted to and executed through mitochondria. Mitochondria are key for both apoptotic and autophagic cell death. Thus ER is vital in sensing and coordinating stress pathways to maintain overall physiological homeostasis. However, this function is deregulated in cancer, resulting in resistance to apoptosis induction in response to various stressors including therapeutic agents. Here we review the connections between ER stress and mitochondrial apoptosis, describing potential cancer therapeutic targets.

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Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells

Cited by 75 publications

References 29 publications

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer

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