HMGB1-mediated autophagy promotes docetaxel resistance in human lung adenocarcinoma

Abstract

BackgroundDocetaxel resistance remains a major obstacle in the treatment of non-small cell lung cancer (NSCLC). High-mobility group box 1 (HMGB1) has been shown to promote autophagy protection in response to antitumor therapy, but the exact molecular mechanism underlying HMGB1-mediated autophagy has not been clearly defined.MethodsLung adenocarcinoma (LAD) cells were transfected with pcDNA3.1-HMGB1 or HMGB1 shRNA, followed by docetaxel treatment. Cell viability and proliferation were tested by MTT assay and colony formation assay, respectively. Annexin V flow cytometric analysis and western blot analysis of activated caspase3 and cleaved PARP were used to evaluate apoptosis, while immunofluorescence microscopy and transmission electron microscopy were applied to assess autophagy activity. The formation of the Beclin-1-PI3K-III complex was examined by immunoprecipitation analysis. NOD/SCID mice were inoculated with docetaxel-resistant SPC-A1/DTX cells transfected with control or HMGB1 shRNA.ResultsHMGB1 translocated from the nucleus to the cytoplasm in LAD cells exposed to docetaxel and acted as a positive regulator of autophagy, which inhibited apoptosis and increased drug resistance. Suppression of HMGB1 restored the sensitivity of LAD cells to docetaxel both in vivo and in vitro. Mechanistic investigation revealed that HMGB1 promoted the formation of the Beclin-1-PI3K-III complex through activating the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating autophagosome formation.ConclusionsOur results demonstrated that HMGB1-regulated autophagy is a significant contributor to docetaxel resistance in LAD cells. Suppression of HMGB1 or limiting HMGB1 cytosolic translocation diminished autophagic protection in response to docetaxel in LAD cells.

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

“…HMGB1 is present at increased levels in NSCLC patients [46]. HMGB1-mediated autophagy has been reported to contribute to acquired NSCLC chemo-resistance [30, 31]. In this study, we found that nutrient deprivation as well as the anticancer drug ADM or DDP induced HMGB1-mediated autophagy of NSCLC cells.…”

“…It has been reported that HMGB1 knockdown by RNA interference inhibits autophagy and promotes chemo-resistance in NSCLC cells [30, 31]. Based on these previous findings, we speculated that miR-142-3p could regulate NSCLC cell autophagy by downregulating HMGB1.…”

“…Intriguingly, recent studies indicate that HMGB1 also promotes chemo-resistance of a number of cancer cells including NSCLC by activating protective autophagy [27-31]. In particular, suppression of HMGB1 sensitizes NSCLC cells to docetaxel and cisplatin by inhibiting autophagy and increasing apoptosis [30, 31]. Thus, targeting HMGB1-mediated autophagy might have clinical significance in NSCLC treatment.…”

Blockade Efficacy of MEK/ERK-Dependent Autophagy Enhances PI3K/Akt Inhibitor NVP-BKM120's Therapeutic Effectiveness in Lung Cancer Cells

“…In addition to the negative regulation of autophagy by the class I PI3K/Akt/mTORC1 signaling [24][25][26][27][28], the MEK/ERK signaling is suggested to be involved in positive regulation of autophagy [29][30][31][32]. In the study, we could detect increased levels of p-ERK1/2…”

Establishment of a highly metastatic model with a newly isolated lung adenocarcinoma cell line

“…Doxorubicin (42,43) and docetaxel (44)(45)(46)(47), which are commonly used as chemotherapy regimens for advanced non-small cell lung cancer (NSCLC), were introduced in the drug-sensitive of Xl-2 cells. As shown in Fig.…”