Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer

Sui, Xinbing; Kong, Na; Zhu, Minghua; Wang, Xian; Lou, Fang; Han, Weidong; Pan, Hongming

doi:10.3892/mco.2013.187

Cited by 29 publications

(26 citation statements)

References 48 publications

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“…Numerous studies have implicated the crucial role of autophagy in cancer chemoresistance (Duffy et al., 2015). However, the exact mechanisms underlying this phenomenon are still unknown and represent a significant barrier to the improvement of the long‐term overcome of NSCLC patients (Kovarik et al., 2014; Sui et al., 2014). Our study highlights for the first time the involvement of autophagy in the metastatic mechanism that drives lung cancer immunosuppressive metastasis and inhibits T cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibition upregulates CD4+ tumor infiltrating lymphocyte expression via miR‐155 regulation and TRAIL activation

et al. 2016

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A B S T R A C TChemoresistance is a major challenge in lung cancer treatment. Recent findings have revealed that autophagic mechanism contributes significantly to immunosuppressive related chemoresistance. For that reason, targeting autophagy-related immunosuppression is an important approach to reverse tumor drug resistance. In this study, we report for the first time that autophagy inhibition triggers upregulation of CD4 þ , Foxp3 þ tumor infiltrating lymphocytes in late metastatic lung cancer tissues. Furthermore, autophagy blockage induces chemosensitization to carboplatin, immune activation and cell cycle arrest. This induction correlated with reduction in expression of drug resistance genes MDR1, MRP1, ABCG2 and ABCC2 along with decreased expression of PD-L1 which is associated with severe dysfunction of tumor specific CD8 þ T cells. Furthermore, experiments revealed that co-treatment of carboplatin and autophagy inhibitor chloroquine increased lung tissue infiltration by CD4 þ , FoxP3 þ lymphocytes and antigen-specific immune activation.

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Section: Discussionmentioning

confidence: 99%

Autophagy inhibition upregulates CD4+ tumor infiltrating lymphocyte expression via miR‐155 regulation and TRAIL activation

et al. 2016

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“…We found that nintedanibinduced autophagy is ATG7 independent and beclin-1 dependent and thus represents a noncanonical pathway (17,34). Several (37,38) and lymphangioleiomyomatosis (39). Whether such an approach would be beneficial in IPF deserves further study.…”

Section: Discussionmentioning

confidence: 99%

Novel Mechanisms for the Antifibrotic Action of Nintedanib

Rangarajan

Kurundkar

et al. 2016

Am J Respir Cell Mol Biol

178

121

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Idiopathic pulmonary fibrosis (IPF) is a disease with relentless course and limited therapeutic options. Nintedanib (BIBF-1120) is a multiple tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of IPF. The precise antifibrotic mechanism(s) of action of nintedanib, however, is not known. Therefore, we studied the effects of nintedanib on fibroblasts isolated from the lungs of patients with IPF. Protein and gene expression of profibrotic markers were assessed by Western immunoblotting and real-time PCR. Autophagy markers and signaling events were monitored by biochemical assays, Western immunoblotting, microscopy, and immunofluorescence staining. Silencing of autophagy effector proteins was achieved with small interfering RNAs. Nintedanib down-regulated protein and mRNA expression of extracellular matrix (ECM) proteins, fibronectin, and collagen 1a1 while inhibiting transforming growth factor (TGF)-b1-induced myofibroblast differentiation. Nintedanib also induced beclin-1-dependent, ATG7-independent autophagy. Nintedanib's ECM-suppressive actions were not mediated by canonical autophagy. Nintedanib inhibited early events in TGF-b signaling, specifically tyrosine phosphorylation of the type II TGF-b receptor, activation of SMAD3, and p38 mitogen-activated protein kinase. Nintedanib down-regulates ECM production and induces noncanonical autophagy in IPF fibroblasts while inhibiting TGF-b signaling. These mechanisms appear to be uncoupled and function independently to mediate its putative antifibrotic effects.

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“…Autophagy inhibition can overcome both the innate and acquired drug resistance of NSCLC, and thus represents a novel strategy to broaden the spectrum of NSCLC treatment [42-44]. In particular, autophagy inhibition has been exploited to improve the efficacy of small-molecule EGFR-tyrosine kinase inhibitors in the treatment of NSCLC patients [39, 44]. Autophagy inhibitors in current NSCLC clinical trials include hydroxychloroquine (HCQ) and chloroquine (CQ) [39].…”

Section: Discussionmentioning

confidence: 99%

MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMGB1-Mediated Autophagy

Chen

Zhou

Qiao

et al. 2017

Cell Physiol Biochem

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Background: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. Methods: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo. HMGB1 was identified as a putative target gene of miR-142-3p by in silico analysis. Our luciferase reporter assay results confirmed that miR-142-3p directly targets the 3’-UTR of HMGB1 in NSCLC cells. Results: MiR-142-3p overexpression suppressed while miR-142-3p knockdown increased HMGB1 mRNA and protein expression. Starvation induced HMGB1 expression and activated autophagy in NSCLC cells. The starvation-induced autophagy was inhibited by miR-142-3p overexpression or HMGB1 knockdown. Moreover, miR-142-3p overexpression or HMGB1 knockdown increased PI3K, Akt, and mTOR phosphorylation. Inhibition of PI3K or mTOR restored starvation-induced autophagy inhibited by miR-142-3p overexpression or HMGB1 knockdown. Conclusions: These results demonstrated that miR-142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3K/Akt/mTOR pathway. Further, miR-142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo. These findings shed light on the therapeutic potential of miR-142-3p in combating acquired NSCLC chemo-resistance.

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Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer

Cited by 29 publications

References 48 publications

Autophagy inhibition upregulates CD4+ tumor infiltrating lymphocyte expression via miR‐155 regulation and TRAIL activation

Autophagy inhibition upregulates CD4+ tumor infiltrating lymphocyte expression via miR‐155 regulation and TRAIL activation

Novel Mechanisms for the Antifibrotic Action of Nintedanib

MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMGB1-Mediated Autophagy

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