Dual PI3K/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines is enhanced by inhibitors of autophagy

Chang, Zhenyu; Shi, Guang; Jin, Jiye; Guo, Hao; Guo, Xuefeng; Luo, Fangyue; Song, Yi; Jia, Xiaojing

doi:10.3892/ijmm.2013.1351

Cited by 56 publications

(44 citation statements)

References 32 publications

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“…In addition, inhibition of the PI3K/AKT/mTOR signaling pathway can result in the induction of autophagy [22]. Some studies have shown that inhibition of autophagy might overcome the therapeutic resistance to PI3K/AKT/mTOR signaling inhibitors in some types of tumors [39–41]. Similar results were also observed in our study, which showed that addition of the autophagy inhibitor CQ enhanced matrine-induced cell apoptosis.…”

Section: Discussionsupporting

confidence: 88%

Blocking Autophagic Flux Enhances Matrine-Induced Apoptosis in Human Hepatoma Cells

Wang

Gao

Yao

et al. 2013

IJMS

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Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC). Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V–FITC/PI double-staining assay), the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1) both autophagy and apoptosis could be induced by treatment with matrine; (2) using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3) autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

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Section: Discussionsupporting

confidence: 88%

Blocking Autophagic Flux Enhances Matrine-Induced Apoptosis in Human Hepatoma Cells

Wang

Gao

Yao

et al. 2013

IJMS

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“…Akt activates mTOR by phosphorylating Ser2448 sites of mTOR to enhance the efficiency of mRNA translation, thereby increasing the expression of proteins associated with cell growth and differentiation, and accelerating tumorigenesis (20). The present study revealed that silybin treatment reduced the protein levels of p-mTOR in U266 cells in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 48%

Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway

Feng

Luo

Guo

2016

Molecular Medicine Reports

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Abstract. Silybin is a biologically active component extracted from the seeds of Silybum marianum, which has been shown to have inhibitory effects on prostate, skin, bladder, lung and colon cancer cells, in addition to its efficacy in the treatment of liver diseases, including hepatitis and cirrhosis. The aim of the present study was to investigate whether silybin suppresses the proliferation and induces apoptosis of multiple myeloma (MM) cells and to elucidate its molecular targets. The proliferative and apoptotic rates of the U266 MM cell line were assessed using MTT and flow-cytometric assays, respectively. Western blot analysis was used to assess the protein levels of phosphoinositide-3 kinase (PI3K), phosphorylated (p)-Akt and p-mammalian target of rapamycin (mTOR) in U266 cells. In addition, PI3K inhibitor LY294002 or activator insulin-like growth factor 1 were used to investigate the involvement of the PI3K/Akt-mTOR signaling pathway in the effect of silybin on U266 cells. The results revealed that silybin restrained the proliferation and enhanced the apoptosis of U266 cells. Furthermore, silybin inhibited the protein expression of PI3K, p-Akt and p-mTOR in U266 cells. Of note, inhibition of PI3K facilitated silybin-mediated reduction of mTOR activation, cell proliferation and induction of apoptosis in U266 cells, while activation of PI3K attenuated the effects of silybin. In conclusion, silybin suppressed cell proliferation and promoted apoptosis of U266 cells via PI3K/Akt-mTOR signaling pathways.

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“…Chang et al (24) reported that dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines was enhanced by inhibition of autophagy. In the present study, it was observed that knockdown of STMN1 led to upregulation of mTOR signaling, which additionally inhibited autophagy.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of STMN1 enhances osteosarcoma cell chemosensitivity through inhibition of autophagy

Wang

Xia

et al. 2017

Oncology Letters

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Chemoresistance is a major cause for the poor prognosis of osteosarcoma (OS) patients. However, our understanding of mechanisms underlying chemoresistance in OS are limited. The present study aimed to investigate the effect of stathmin 1 (STMN1) on paclitaxel-induced chemoresistance, as well as the underlying mechanism. Western blot analysis data revealed that the expression level of STMN1 was dramatically increased in OS cell lines (HOS, Saos-2, U-2OS and MG-63), when compared to normal osteoblast hFOB1.19 cells. Furthermore, treatment with paclitaxel led to upregulation of STMN1 in U-2OS cells, accompanied by activation of autophagy, which may attenuate the cytotoxicity of paclitaxel in OS cells. Following knockdown of STMN1 expression, paclitaxel-induced autophagy was significantly reduced, accompanied by increased cytotoxicity of paclitaxel to U-2OS cells. In addition, blockade of mammalian target of rapamycin signaling attenuated the inhibitory effect of STMN1 knockdown on autophagy in OS cells. In conclusion, the present study demonstrated that knockdown of STMN1 enhances osteosarcoma cell chemosensitivity to paclitaxel through inhibition of autophagy. Therefore, STMN1 may be a potential target for the treatment of chemoresistant OS.

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Dual PI3K/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines is enhanced by inhibitors of autophagy

Cited by 56 publications

References 32 publications

Blocking Autophagic Flux Enhances Matrine-Induced Apoptosis in Human Hepatoma Cells

Blocking Autophagic Flux Enhances Matrine-Induced Apoptosis in Human Hepatoma Cells

Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway

Knockdown of STMN1 enhances osteosarcoma cell chemosensitivity through inhibition of autophagy

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