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;


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

Download this article


    [1] Ministry of Health of the People’s Republic of China. 第三次全国死因调查主要情况 [J]. China Cancer, 2008, 17 (5): 344 (in Chinese).

    [2] Yuan Y, Wu Q, Shi JS, et al. Advance in studies on hepatoprotective effect of Salvia miltiorrhiza and its main components [J]. China Journal of Chinese Materia Medica, 2015, 40 (4): 588 (in Chinese).

    [3] Liang WY, Chen WJ, Yang GH, et al. Research progress on salvianolic acids of Salvia miltiorrhiza [J]. China Journal of Chinese Materia Medica, 2016, 41 (5): 806 (in Chinese).

    [4] Chiu T L, Su C C. Tanshinone ⅡA induces apoptosis in human lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential [J]. Int J Mol Med, 2010, 25 (2): 231.

    [5] Chen W, Luo Y, Liu L, et al. Cryptotanshinone inhibits cancer cell proliferation by suppressing Mammalian target of rapamycin mediated cyclinD1 expression and Rb phoshorylation [J]. Cancer Prev Res (Phila), 2010, 3 (8): 1015.

    [6] Lou ZH, Yang B, Shen W, et al. Studies on HSCCC preparation technology of diterpenoidtanshinone and its antitumor activity in vitro [J]. Chinese Traditional and Herbal Drugs, 2015, 46 (5): 679 (in Chinese).

    [7] Rao XQ. 中医中药治疗肿瘤近况 [J]. The Journal of Medical Theory and Practice, 1999 (2): 61 (in Chinese).

    [8] Wang SM, Jin CJ. 中药治疗原发性肺癌的药味频率分析 [J]. Liaoning Journal of Traditional Chinese Medicine, 2010, 37 (11): 2122 (in Chinese).

    [9] Yan ZH. 中药学 [M]. Beijing: People’s Medical Publishing House, 2006: 634 (in Chinese).

    [10] Chen C, Wang HJ, Liu FR, et al. Preparation and antitumor effects of tanshinone ⅡA loaded albumin nanoparticles [J]. China Journal of Chinese Materia Medica, 2017, 42 (4): 696 (in Chinese).

    [11] Yu J, Wang X X, Li Y H, et al. Tanshinone ⅡA suppresses gastric cancer cell proliferation and migration by downregulation of FOXM1 [J]. Oncol Rep, 2017, 37: 1394.

    [12] Yun S M, Jung J H, Jeong S J, et al. Tanshinone ⅡA induces autophagic cell death via activation of AMPK and ERK and inhibition of m TOR and p70 S6K in KBM-5 leukemia cells [J]. Phytother Res, 2014, 28 (3): 458.

    [13] Liu J J, Lin D J, Liu P Q, et al. Induction of apoptosis and inhibition of cell adhesive and invasive effects by tanshinone ⅡA in acute promyelocytic leukemia cells in vitro [J]. J Biomed Sci, 2006, 12 (6): 813.

    [14] Pan T L, Wang P W, Huang Y C, et al. Proteomic analysis reveals tanshinone ⅡA enhances apoptosis of advanced cervix carcinoma CaSki cells through mitochondria intrinsic and endoplasmic reticulum stress pathways [J]. Proteomics, 2013, 274: 3411.

    [15] Deng FC, Yu ZJ, Yang Y, et al. Effect and mechanism of cryptotanshinone on apoptosis of human gastric cancer cell line SGC-7901 [J]. Journal of Beijing University of Traditional Chinese Medicine, 2015, 38 (7): 457 (in Chinese).

    [16] Zhu ZJ, Liu ZG, Zhou L, et al. 隐丹参酮对人乳腺癌细胞MDAMB-231转移的影响及其分子机制 [J]. Chinese Journal of Experimental Traditional Medical Formulae, 2014, 20 (11): 160 (in Chinese).

    [17] Song Y. The Study on the Anti-tumor Activity of Tanshinone I and Dihydrotan-shinone I on MCF-7 Human Breast and MGC-803 Gastric Cancer Cell Lines [J]. Journal of Mathematical Medicine, 2015, 28 (6): 803 (in Chinese).

    [18] Yuan YF, Yang HL. Endoplasmic reticulum stress and apoptosis of tumor cells [J]. Journal of Molecular Diagnostics and Therapy, 2010, 2 (3): 128 (in Chinese).

    [19] Jiang Q, Xu CM. 内质网应激与细胞死亡 [J]. Chemistry of Life, 2009, 29 (5): 645 (in Chinese).

    [20] Zheng H. 内质网应激介导的细胞死亡与肿瘤治疗进展 [J]. Cancer Research on Prevention and Treatment, 2013, 40 (2): 197 (in Chinese).

    [21] Ma LY, Li L, Jiang Y, et al. Sasanguasaponin-indúced apoptosis of Jurkat cells through endoplasmic reticulum stress [J]. Chinese Traditional Patent Medicine, 2012, 34 (3): 430 (in Chinese).

    [22] Ye YQ, Li GP, Pu ZJ, et al. 腺苷通过内质网应激途径诱导HepG2细胞凋亡的研究 [J]. Chinese Pharmacological Bulletin, 2010, 26 (5): 596 (in Chinese).

    [23] Gao CC, Lu HY. 内质网应激与相关肺疾病 [J]. Journal of Medical Research, 2012, 41 (12): 196 (in Chinese).

    [24] Li X, Zhang K, Li Z. Unfolded protein response in cancer:the physician’s perspective [J]. J Hematol Oncol, 2011, 4: 8.

    [25] Knowlton A A. Life, death, the unfolded protein response and apoptosis [J]. Cardiovascular Res, 2007, 73 (1): 1.

    [26] Lin J H, Li H, Yasumura D, et al. IRE1 signaling affects cell fate during the unfolded protein response [J]. Science, 2007, 318: 944.

    [27] Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloidbeta [J]. Nature, 2000, 403 (6765): 98.

    [28] Kurokawa M, Kornbluth S. Caspases and kinases in a death grip [J]. Cell, 2009, 138 (5): 838.

    [29] Hitomi J, Katayama T, Taniguchi M, et al. Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12 [J]. Neurosci Lett, 2004, 357 (2): 127.

    [30] Li XJ, Xia RM, Lou ZH, et al. 丹参二萜醌通过PERK-EIF2α通路诱导PC9细胞凋亡的机制研究 [J]. China Journal of Traditional Chinese Medicine and Pharmacy, 2017, 32 (5): 1897 (in Chinese).

This Article


CN: 11-2272/R

Vol 43, No. 24, Pages 4900-4907

December 2018


Article Outline


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