title: (Z)3,4,5,4'-trans-tetramethoxystilbene, a new analogue of resveratrol, inhibits gefitinb-resistant non-small cell lung cancer via selectively elevating intracellular calcium level.
abstract: Calcium is a second messenger which is required for regulation of many cellular processes. However, excessive elevation or prolonged activation of calcium signaling would lead to cell death. As such, selectively regulating calcium signaling could be an alternative approach for anti-cancer therapy. Recently, we have identified an effective analogue of resveratrol, (Z)3,4,5,4'-trans-tetramethoxystilbene (TMS) which selectively elevated the intracellular calcium level in gefitinib-resistant (G-R) non-small-cell lung cancer (NSCLC) cells. TMS exhibited significant inhibitory effect on G-R NSCLC cells, but not other NSCLC cells and normal lung epithelial cells. The phosphorylation and activation of EGFR were inhibited by TMS in G-R cells. TMS induced caspase-independent apoptosis and autophagy by directly binding to SERCA and causing endoplasmic reticulum (ER) stress and AMPK activation. Proteomics analysis also further confirmed that mTOR pathway, which is the downstream of AMPK, was significantly suppressed by TMS. JNK, the cross-linker of ER stress and mTOR pathway was significantly activated by TMS. In addition, the inhibition of JNK activation can partially block the effect of TMS. Taken together, TMS showed promising anti-cancer activity by mediating calcium signaling pathway and inducing apoptosis as well as autophagy in G-R NSCLC cells, providing strategy in designing multi-targeting drug for treating G-R patients.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Xing-Xing
authors.initials: XX
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Su Wei
authors.initials: SW
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Vincent Kam-Wai
authors.initials: VK
authors.lastname: Wong
authors.affiliation: Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical College, Guangzhou, China.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: He
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academic of Sciences, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Xue
authors.affiliation: Department of Biological Sciences, University of Chester, Chester, United Kingdom.
authors.forename: Tahira
authors.initials: T
authors.lastname: Mujtaba
authors.affiliation: Department of Biological Sciences, University of Chester, Chester, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelangeli
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academic of Sciences, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical College, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical College, Guangzhou, China.
authors.forename: Da-Kai
authors.initials: DK
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Ze-Bo
authors.initials: ZB
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhou
authors.affiliation: Department Chemical Pathology, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong (SAR), China.
authors.forename: Richard Kin-Ting
authors.initials: RK
authors.lastname: Kam
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Elaine Lai-Han
authors.initials: EL
authors.lastname: Leung
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C482492:3,4,5,4'-tetramethoxystilbene; D000970:Antineoplastic Agents; D011799:Quinazolines; D013267:Stilbenes; D066246:ErbB Receptors; D000263:Adenylate Kinase; D000077156:Gefitinib; D002118:Calcium