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Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.

ABSTRACT: Autophagy is an evolutionarily conserved survival pathway in eukaryote and is frequently upregulated in cancer cells after chemotherapy or targeted therapy. Thus induction of autophagy has emerged as a drug resistance mechanism. In this study, we found that crizotinib induced a high level of autophagy in lung cancer cells through inhibition of STAT3. Ectopic expression of wild-type or constitutive activated STAT3 significantly suppressed the effect of crizotinib on autophagy. Interestingly, crizotinib-mediated inhibition of STAT3 is in a step-wise manner. Firstly it inhibited cytoplasmic STAT3, which leads to the phosphorylation of EIF2A, then inhibited nuclear STAT3, which leads to the downregulation of BCL-2. Cell death induced by crizotinib was greatly enhanced after the inhibition of autophagy by the pharmacological inhibitors or shRNAs against Beclin-1. Moreover, the autophagy inhibitor HCQ significantly augmented the anti-tumor effect of crizotinib in a mouse xenograft model. In conclusion, crizotinib can induce cytoprotective autophagy by suppression of STAT3 in lung cancer cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of crizotinib in the treatment of targeted lung cancer patients.

SUBMITTER: You L

PROVIDER: S-EPMC4741894 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.

You Liangkun L Shou Jiawei J Deng Danchen D Jiang Liming L Jing Zhao Z Yao Junlin J Li Hongsen H Xie Jiansheng J Wang Zhanggui Z Pan Qin Q Pan Hongming H Huang Wendong W Han Weidong W

Oncotarget 20151101 37

Autophagy is an evolutionarily conserved survival pathway in eukaryote and is frequently upregulated in cancer cells after chemotherapy or targeted therapy. Thus induction of autophagy has emerged as a drug resistance mechanism. In this study, we found that crizotinib induced a high level of autophagy in lung cancer cells through inhibition of STAT3. Ectopic expression of wild-type or constitutive activated STAT3 significantly suppressed the effect of crizotinib on autophagy. Interestingly, criz ...[more]

PMID: 26384345

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Project description:Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM.

Project description:BackgroundCrizotinib has potent anti-tumor activity in patients with advanced MET-amplified non-small cell lung cancer (NSCLC). However, the therapeutic effect is still not satisfying. Thus, developing approaches that improve the efficacy of crizotinib remains a significant challenge.MethodsMET-amplified NSCLC cell lines were treated with crizotinib and cyclosporine A (CsA). Cell viability was determined by MTS assay. The changes of apoptosis, cell cycle and calcineurin-Erk pathways were assessed by western blot. Xenograft mouse model, primary human NSCLC cells and hollow fiber assays were utilized to confirm the effects of CsA.FindingsWe demonstrated that CsA significantly increased the anti-tumor effect of crizotinib on multiple MET-amplified NSCLC cells in vitro and in vivo. Mechanistically, crizotinib treatment led to the activation of Ca2+-calcineurin (CaN)-Kinase suppressor of Ras 2 (KSR2) signaling, resulting in Erk1/2 activation and enhanced survival of cancer cells. CsA effectively blocked CaN-KSR2-Erk1/2 signaling, promoting crizotinib-induced apoptosis and G2/M arrest. Similarly, pharmacologic or genetic inhibition of Erk1/2 also enhanced crizotinib-induced growth inhibition in vitro. Xenograft studies further confirmed that CsA or Erk1/2 inhibitor PD98059 enhanced the anti-cancer activity of crizotinib through inhibition of CaN-Erk1/2 axis. The results were also validated by primary human NSCLC cells in vitro and hollow fiber assays in vivo.InterpretationThis study provides preclinical evidences that combination therapy of CsA and crizotinib is a promising approach for targeted treatment of MET-amplified lung cancer patients. FUND: This work was supported by the National Natural Science Foundation of China, the Key Projects of Natural Foundation of Zhejiang Province, the Ten thousand plan youth talent support program of Zhejiang Province, the Zhejiang Natural Sciences Foundation Grant, and the Zhejiang medical innovative discipline construction project-2016.

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Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.

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Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.

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