Autophagy induction contributes to GDC-0349 resistance in head and neck squamous cell carcinoma (HNSCC) cells.
Dysregulation of mammalian target of rapamycin (mTOR) signaling contributes to head and neck squamous cell carcinoma (HNSCC) tumorigenesis and progression. In the current study, we tested the anti-HNSCC cell activity by GDC-0349, a selective ATP-competitive inhibitor of mTOR. We showed that GDC-0349 inhibited proliferation of established and primary human HNSCC cells bearing high-level of p-AKT/p-S6K. Further, it induced caspase-dependent apoptosis in the HNSCC cells. GDC-0349 blocked mTORC1 and mTORC2 activation, yet it simultaneously induced autophagy activation in HNSCC cells. The latter was evidenced by induction of LC3B-II, Beclin-1 and Autophagy-related (ATG)-7, as well as downregulation of p62. Autophagy inhibitors (3-methyladenine and bafilomycin A1) or ATG-7 siRNA dramatically potentiated GDC-0349's cytotoxicity against HNSCC cells. Intriguingly, we showed that ceramide (C14), a pro-apoptotic sphingolipid, also induced ATG-7 degradation, and sensitized HNSCC cells to GDC-0349. Collectively, the preclinical study provided evidences to support GDC-0349 as a promising anti-HNSCC agent. GDC-0349 sensitization may be achieved via autophagy inhibition.
Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, China.
Yajuan
Y
Zhou
Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, China.
Yi
Y
Peng
Department of Pathology, Hubei Cancer Hospital, Wuhan 430071, China.
Hao
H
Tang
Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, China.
Xiaojun
X
He
Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, China.
Zhaohua
Z
Wang
Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, China. Electronic address: hudeshengvvip@sina.com.
Desheng
D
Hu
Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, China. Electronic address: zhouxy1218@126.com.
Xiaoyi
X
Zhou
D001343:Autophagy / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
C000620512:GDC-0349; D010671:Phenylurea Compounds; D011743:Pyrimidines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
ATG-7; Autophagy; GDC-0349; Head and neck squamous cell carcinoma (HNSCC); mTOR