Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis.
Ying Hong Shi,Zhen-Bin Ding,Jian Zhou,Bo Hui,Guo-Ming Shi,Ai-Wu Ke,Xiaoying Wang,Zhi Dai,Yuan Fei Peng,Cheng Yu Gu,Shuang Jian Qiu,Jia Fan +11 more
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TLDR
Findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells, indicating that the combination of Autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.Abstract:
Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both ...read more
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Journal ArticleDOI
miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions.
Ying Chang,Ying Chang,Wei Yan,Xing-Xing He,Lemeng Zhang,Chuanjiang Li,Hai Huang,Gary W. Nace,David A. Geller,Ju-Sheng Lin,Allan Tsung +10 more
TL;DR: The role of microRNAs (miRNAs) in regulating autophagy of hepatocellular carcinoma (HCC) cells under hypoxic conditions was investigated in this article.
Journal ArticleDOI
Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma
Bo Zhai,Fengli Hu,Xian Jiang,Jun Xu,Dali Zhao,Bing Liu,Shangha Pan,Xuesong Dong,Gang Tan,Zheng Wei,Haiquan Qiao,Hongchi Jiang,Xueying Sun +12 more
TL;DR: Results have provided evidence for clinical investigation of GDC0068, a novel ATP-competitive pan-Akt inhibitor, as the second-line treatment after the failure of sorafenib-medicated molecular targeted therapy for advanced HCC.
Journal ArticleDOI
Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC
Lai Wei,Lai Wei,Derek Lee,Derek Lee,Cheuk-Ting Law,Cheuk-Ting Law,Misty Shuo Zhang,Misty Shuo Zhang,Jialing Shen,Jialing Shen,Don Wai-Ching Chin,Don Wai-Ching Chin,Allen Zhang,Allen Zhang,Felice Ho-Ching Tsang,Felice Ho-Ching Tsang,Ceci Lok-Sze Wong,Ceci Lok-Sze Wong,Irene Oi-Lin Ng,Irene Oi-Lin Ng,Carmen Chak-Lui Wong,Carmen Chak-Lui Wong,Chun-Ming Wong,Chun-Ming Wong +23 more
TL;DR: It is shown that phosphoglycerate dehydrogenase, a key enzyme in the serine synthesis pathway, drives sorafenib resistance, which is a major clinical challenge to overcome TKI drug resistance in HCC.
Journal ArticleDOI
Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells
Yuan-Fei Peng,Ying-Hong Shi,Zhen-Bin Ding,Ai-Wu Ke,Cheng-Yu Gu,Bo Hui,Jian Zhou,Shuang-Jian Qiu,Zhi Dai,Jia Fan +9 more
TL;DR: Investigation of the molecular mechanisms underlying showed that the autophagy-inhibition-mediated anoikis-resistance attenuation was associated with the regulation of apoptotic signaling, and an autophile-based HCC tissue-specific target therapy system (AFP-Cre/LoxP-shRNA) was constructed.
Journal ArticleDOI
Autophagy Inhibition Sensitizes Colon Cancer Cells to Antiangiogenic and Cytotoxic Therapy
TL;DR: Findings implicate autophagy as a mechanism of resistance to antiangiogenic therapies and support investigation of inhibitory approaches in the management of this disease.
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