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Published on: September 8, 2017
HMGB1-mediated autophagy promotes docetaxel resistance in human lung adenocarcinoma
Banzhou Pan, Dongqin Chen, Jiayuan Huang
1Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, P,R, China. songhaizhu@163.com.
Background:
Docetaxel 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.
Methods:
Lung 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.
Results:
HMGB1 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.
Conclusions:
Our 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.
Insights
High-mobility group box 1 (HMGB1) promotes autophagy, increasing docetaxel resistance in lung cancer. Suppressing HMGB1 restores drug sensitivity by inhibiting this protective autophagy mechanism.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Docetaxel resistance is a significant challenge in non-small cell lung cancer (NSCLC) treatment.
- High-mobility group box 1 (HMGB1) is implicated in autophagy-mediated chemoresistance, but its precise role is unclear.
Purpose of the Study:
- To elucidate the molecular mechanism of HMGB1-regulated autophagy in docetaxel resistance in lung adenocarcinoma (LAD).
- To investigate the potential of targeting HMGB1 to overcome docetaxel resistance.
Main Methods:
- Investigated HMGB1 translocation, autophagy markers (Beclin-1, PI3K-III complex), apoptosis (caspase-3, PARP), and cell viability (MTT, colony formation) in docetaxel-treated LAD cells.
- Utilized gene silencing (shRNA) and overexpression (pcDNA3.1-HMGB1) of HMGB1.
- Examined the MEK-ERK signaling pathway and performed in vivo studies using NOD/SCID mice.
Main Results:
- Docetaxel induced HMGB1 nuclear-to-cytoplasmic translocation, promoting autophagy and conferring docetaxel resistance.
- HMGB1 suppression restored docetaxel sensitivity in vitro and in vivo.
- HMGB1 activation of the MEK-ERK pathway facilitated Beclin-1-PI3K-III complex formation, driving autophagosome synthesis.
Conclusions:
- HMGB1-driven autophagy is a key mechanism of docetaxel resistance in LAD cells.
- Inhibiting HMGB1 or its cytosolic translocation can overcome chemoresistance by reducing autophagic protection.
