title: Autophagic degradation of epidermal growth factor receptor in gefitinib-resistant lung cancer by celastrol.
abstract: Drug resistance of non-small cell lung cancer (NSCLC) is highly correlated to the mutation of the epidermal growth factor receptor (EGFR). Although EGFR tyrosine kinase inhibitors (TKIs) are available clinically, the molecular complexity of NSCLC has made it necessary to search for alternative therapeutic approaches to overcome the drug resistance of NSCLC. In the present study, we identified a triterpene molecule derived from the herbal plant Tripterygium wilfordii, celastrol, as a novel autophagy inducer. We demonstrate that celastrol exhibited selective cytotoxic effect towards EGFR mutant NSCLCs. In addition, celastrol also facilitated the autophagic degradation of Hsp90 client protein including EGFR and Akt on both EGFR wild-type and mutant NSCLCs via calcium-mediated autophagy. Blockage of celastrol-induced autophagic degradation of EGFR by autophagic inhibitor or calcium chelator decreased celastrol-mediated cell death in gefitinib-resistant NSCLCs. Overall, our findings suggest that celastrol may be developed as an effective anticancer agent for treatment of gefitinib-resistant NSCLC in the future.
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Su-Wei
authors: SW
authors: Xu
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Betty Yuen Kwan
authors: BY
authors: Law
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Simon Wing Fai
authors: SW
authors: Mok
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Elaine Lai Han
authors: EL
authors: Leung
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Xing Xing
authors: XX
authors: Fan
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Paolo Saul
authors: PS
authors: Coghi
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Wu
authors: W
authors: Zeng
authors: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, P.R. China.
authors: Chung-Hang
authors: CH
authors: Leung
authors: Department of Chemistry, Hong Kong Baptist University, Hong Kong, P.R. China.
authors: Dik-Lung
authors: DL
authors: Ma
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Liang
authors: L
authors: Liu
authors: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
authors: Vincent Kam Wai
authors: VK
authors: Wong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053978:Pentacyclic Triterpenes; D059748:Proteolysis / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D011799:Quinazolines; D014315:Triterpenes; C512478:EGFR protein, human; D066246:ErbB Receptors; C050414:celastrol; D000077156:Gefitinib