(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

• Published in: Scientific reports Vol. 5; no. 1; p. 16348
• Main Authors: Fan, Xing-Xing, Yao, Xiao-Jun, Xu, Su Wei, Wong, Vincent Kam-Wai, He, Jian-Xing, Ding, Jian, Xue, Wei-Wei, Mujtaba, Tahira, Michelangeli, Francesco, Huang, Min, Huang, Jun, Xiao, Da-Kai, Jiang, Ze-Bo, Zhou, Yan-Ling, Kam, Richard Kin-Ting, Liu, Liang, Leung, Elaine Lai-Han
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.11.2015; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/95; 14; 14/34; 631/67/1612; 692/308/153; 82; Adenylate Kinase - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Ca2+-transporting ATPase; Calcium (intracellular); Calcium - metabolism; Calcium signalling; Caspase; Cell death; Cell Line, Tumor; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Enzyme Activation; Epidermal growth factor receptors; Epithelial cells; Gefitinib; Humanities and Social Sciences; Humans; Intracellular; JNK protein; Lung cancer; multidisciplinary; Non-small cell lung carcinoma; Phagocytosis; Phosphorylation; Proteomics; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Resveratrol; Science; Signal transduction; Small cell lung carcinoma; Stilbenes - chemistry; Stilbenes - pharmacology; TOR protein
• DOI: 10.1038/srep16348
• ISSN: 2045-2322

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.