Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

Xu, Ning; Zhang, Jianjun; Shen, Chen; Luo, Yi; Xia, Lei; Xue, Feng; Xia, Qiang

doi:10.1016/j.bbrc.2012.06.048

Cited by 178 publications

(126 citation statements)

References 21 publications

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“…Activation of autophagy is involved in the resistance to cisplatin (19), whereas inhibition of autophagy enhances the effect of sorafenib (20,21) in HCC cells. However, the role of autophagy and its cross-talk with other pathways in mediating resistance to sorafenib of HCC have not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Zhai

Jiang

et al. 2014

Molecular Cancer Therapeutics

246

234

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Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but the acquired resistance to sorafenib results in limited benefits. Activation of Akt is thought to be responsible for mediating the acquired resistance to sorafenib. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance. Two sorafenib-resistant HCC cell lines, which had been established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure to sorafenib activated Akt via the feedback loop of mTOR but independent of protein phosphatase 2A in HCC cells. Autophagy participated in the resistance to sorafenib as inhibition of autophagy reduced the sensitivity of sorafenib-resistant HCC cells to sorafenib, whereas activation of autophagy by rapamycin had the opposite effect. However, rapamycin did not show a synergistic effect with sorafenib to inhibit cell proliferation, while it also activated Akt via a feedback mechanism in sorafenib-resistant HCC cells. Inhibition of Akt reversed the acquired resistance to sorafenib by switching autophagy from a cytoprotective role to a death-promoting mechanism in the sorafenib-resistant HCC cells. Akt inhibition by GDC0068 synergized with sorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant feature in vivo. The 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. Mol Cancer Ther; 13(6); 1589-98. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Zhai

Jiang

et al. 2014

Molecular Cancer Therapeutics

246

234

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“…Thus, miR-122, a key regulator of cholesterol and fatty-acid metabolism, may be an attractive therapeutic target for metabolic diseases, including NASH. miR-199 has been reported to affect the proliferation and apoptosis of hepatoma carcinoma cells (38), and regulates the TGF-β signaling pathway, by directly targeting Smad4 (39). Furthermore, Murakami et al (16) have shown that overexpression of miR-199 is associated with the progression of liver fibrosis.…”

mentioning

confidence: 99%

Upregulated microRNA-199a-5p inhibits nuclear receptor corepressor 1 translation in mice with non-alcoholic steatohepatitis

Zhang

Wang

et al. 2014

Molecular Medicine Reports

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Abstract. Mounting evidence indicates that dysregulated microRNAs (miRNAs) are important in the etiology and pathogenesis of steatohepatitis. However, the functions of miRNAs in the pathophysiological process of non-alcoholic steatohepatitis (NASH) are poorly understood. In this study, C57BL/6J mice were fed a methionine-choline-deficient (MCD) diet for eight weeks in order to induce hepatic steatohepatitis. Using reverse transcription polymerase chain reaction, the hepatic expression levels of miR-199a-5p, miR-122 and miR-221 in the mice were examined. Bioinformatic analysis of dysregulated miR-199a-5p was performed to predict the potential role of miR-199a-5p in NASH. The MCD diet was found to significantly reduce miR-122 expression levels and significantly increase miR-199a-5p expression levels in mouse livers, compared with those of mice fed a control diet. In the bioinformatic analysis, miR-199a-5p was identified to be predominantly involved in transcription, protein serine/threonine kinase activity, insulin signaling, and the Wnt and mitogen-activated protein kinase signaling pathways. The regulation of nuclear receptor corepressor 1 (NCOR1) by miR-199a-5p was also examined by silencing and overexpressing this miRNA in LX-2 cells. The data revealed that NCOR1 protein levels were significantly reduced and enhanced by miR-199a-5p mimic and inhibitor, respectively. These findings suggest a key role for miR-199a-5p in the progression of NASH through inhibition of NCOR1 translation, and provide novel insights into NASH pathogenesis.

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“…It has been reported that autophagy increases the resistance of colorectal cancer stem-like cells to photodynamic therapy-induced apoptosis (1,27,28). Similarly, cisplatin-activated autophagy, involving the activation of ATG7, has been indicated to increase liver cancer cell resistance to cisplatin (29). Eum et al (1) suggested that the inhibition of autophagy may resensitize resistant tumor cells to anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol induces autophagic apoptosis via the lysosomal cathepsin D pathway in human drug‑resistant K562/ADM leukemia cells

et al. 2018

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Abstract. The aim of the present study was to investigate the crosstalk between resveratrol (Res)-induced autophagy and apoptosis, and the molecular pathway by which autophagy leads to apoptotic death in drug-resistant K562/ADM leukemia cells. The viability of K562/ADM cells was determined using the MTT assay. The formation of autophagic vacuoles was detected using transmission electron microscopy and monodansylcadaverine (MDC) staining. Cell apoptosis was evaluated using flow cytometry. The expression of apoptosis-or autophagy-associated proteins was measured using western blotting. The results indicated that treatment with Res inhibited cell viability in a concentration-dependent manner. Furthermore, the numbers of MDC-positive fluorescent points, autophagic vacuoles and autolysosome-engulfed cytoplasmic materials were markedly increased in Res-treated K562/ADM cells compared with untreated cells, as determined using fluorescence microscopy and transmission electron microscopy. Res-induced apoptosis was associated with increased cleaved caspase-3 and B-cell lymphoma 2 associated X protein, and decreased B-cell lymphoma 2 (Bcl-2) protein expression levels when compared with the control (P<0.05). However, the proportion of apoptotic cells decreased from 69.6 to 41.0% (40 µmol/l Res) and from 77.3 to 58.8% (80 µmol/l Res) following pre-treatment with the autophagy inhibitor 3-methyladenine (P<0.01). The protein expression levels of microtubule-associated protein 1A/1B-light chain 3 and beclin 1, two markers of autophagy, were upregulated in Res-treated cells compared with the control (P<0.05). In addition, lysosomal cathepsin D (Cath D) release increased during Res-induced autophagy and apoptosis (P<0.05). The present results demonstrated that Res-induced apoptosis of K562/ADM cells was autophagy-dependent and the released Cath D may trigger caspase-dependent cell death through the Bcl-2 family of proteins. Furthermore, the present data indicate that to enhancement of the autophagy-cathepsin-apoptosis pathway may be an effective approach for overcoming anticancer drug resistance.

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Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

Cited by 178 publications

References 21 publications

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Upregulated microRNA-199a-5p inhibits nuclear receptor corepressor 1 translation in mice with non-alcoholic steatohepatitis

Resveratrol induces autophagic apoptosis via the lysosomal cathepsin D pathway in human drug‑resistant K562/ADM leukemia cells

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