Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 35, Pages 18199-18209Publisher
ELSEVIER
DOI: 10.1074/jbc.M116.717793
Keywords
apoptosis; autophagy; head and neck squamous cell carcinoma (HNSCC); proteasome; protein aggregation; signal transduction; signaling
Categories
Funding
- National Institutes of Health Shared Resources from NCRR [CJX1-443835-WS-29646]
- National Science Foundation Major Research Instrumentation Grant [CHE-0722519]
- National Institutes of Health [P30 CA016042, 5P30AI028697]
- Jonsson Comprehensive Cancer Center
- UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
- UCLA Chancellor's Office
- UCLA Vice Chancellor's Office of Research
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Chemoresistance is a major barrier to effective chemotherapy of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Recently, autophagy, a highly conservative intracellular recycling system, has shown to be associated with chemoresistance in cancer cells. However, little is known about how autophagy plays a role in the development of chemoresistance in HNSCC and how autophagy is initiated when HNSCC cells undergo cytotoxic stress. Here, we report that autophagy was activated when HNSCC cells are treated with the proteasome inhibitor bortezomib, proposed as an alternative chemotherapeutic agent for both primary and cisplatin-resistant HNSCC cells. Ablation of histone deacetylase 6 (HDAC6) expression and its activity in HNSCC cells significantly inhibited autophagy induction by altering the phosphorylation status of mammalian target of rapamycin and enhanced the bortezomib cytotoxicity. Similarly, a combination regimen of bortezomib and the histone deacetylase inhibitor trichostatin A abolished HDAC6 activity and decreased autophagy induction while significantly enhancing bortezomib-induced apoptosis in HNSCC cells. These data uncover a novel molecular mechanism indicating that HDAC6 may serve as a critical causal link between autophagy, apoptosis, and the cell survival response in HNSCC. A combination regimen resulting in regression of autophagy improves chemotherapeutic efficacy, thereby providing a new strategy to overcome chemoresistance and to improve the treatment and survival of HNSCC patients.
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