Anti-lung cancer mechanisms of diterpenoid tanshinone via endoplasmic reticulum stress-mediated apoptosis signaling pathway

LOU Zhao-huan1 XIA Rong-man1 LI Xiao-juan1 CHENG Ru-bin1 SHAO Ke-ding1 ZHANG Guang-ji1

(1.Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China 310053)

【Abstract】At present, lung cancer ranks second and first respectively in the incidence and the mortality among malignant tumors. It is urgent to find out new effective anti-lung cancer drugs with less side effects and relatively defined mechanisms. Endoplasmic reticulum stress (ERS) -mediated apoptosis pathway is an effective way to promote tumor cell apoptosis. Diterpenoid tanshinone (DT), an effective part separated from Salviae Miltiorrhizae Radix et Rhizoma, was found to have an anti-lung cancer effect in previous studies via ERS-induced PERK-EIF2α pathway. In this paper, human lung adenocarcinoma PC9 cell line and nude mouse transplantation tumor model were applied to verify the anti-lung cancer effect of DT in vivo and in vitro, and illuminate the potential mechanism via ERS induced IRE1α/caspase 12 apoptosis pathway. The results showed that in vivo, DT could promote PC9 cell apoptosis in a concentration-dependent manner, up-regulate Bip, IRE1 and TRAF2 protein expressions in tumor tissue, reduce tumor weight and alleviate body weight loss. in vitro, DT inhibited the proliferation of PC9 cell line in a concentration-dependent manner, and destroyed the structure of mitochondria in PC9 cell, promoted Bax, IRE1α, Bip, TRAF2 and caspase 12 protein expressions, and lower Bcl-2 protein expression in a time-dependent manner. DT exhibited a good effect on anti-lung cancer both in vivo and in vitro. The mechanism is related to the activation of ERS-induced IRE1α/caspase 12 apoptosis pathway and the promotion of cell apoptosis. ERS-mediated apoptosis pathway may be an important target of DT on anti-lung cancer.

【Keywords】 Salviae Miltiorrhizae Radix et Rhizoma; diterpenoid tanshinone; lung cancer; endoplasmic reticulum stress; IRE1α/caspase 12 pathway;

【DOI】

【Funds】 Natural Science Foundation of China (81573962) China Postdoctoral Science Foundation (2014M561791) Natural Science Foundation of Zhejiang Province, China (LY17H290005)

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This Article

ISSN:1001-5302

CN: 11-2272/R

Vol 43, No. 24, Pages 4900-4907

December 2018

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Abstract

  • 1 Materials
  • 2 Methods
  • 3 Results
  • 4 Discussion
  • References