Ganoderic acid A exerts antitumor activity against MDA‑MB‑231 human breast cancer cells by inhibiting the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway

Yang,Yuguang; Zhou,Hongfeng; Liu,Wenming; Wu,Jin; Yue,Xiaolong; Wang,Jincai; Quan,Lina; Liu,Hang; Guo,Li; Wang,Zhipeng; Lian,Xin; Zhang,Qingyuan

doi:10.3892/ol.2018.9475

Ganoderic acid A exerts antitumor activity against MDA‑MB‑231 human breast cancer cells by inhibiting the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway

Authors:
- Yuguang Yang
- Hongfeng Zhou
- Wenming Liu
- Jin Wu
- Xiaolong Yue
- Jincai Wang
- Lina Quan
- Hang Liu
- Li Guo
- Zhipeng Wang
- Xin Lian
- Qingyuan Zhang
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Affiliations: Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, P.R. China, Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Medical Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: September 21, 2018 https://doi.org/10.3892/ol.2018.9475
Pages: 6515-6521
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Breast cancer is a common malignant tumor among females, with triple‑negative breast cancer being an important type accounting for 15‑20% of all breast cancer cases. Triple‑negative breast cancer is one of the most aggressive types of cancer without standard adjuvant chemotherapy. Ganoderic acid A (GA‑A) is one of the major bioactive Ganoderma triterpenoids isolated from Ganoderma, which are recognized for their preventative and therapeutic effects. In the present study, the antineoplastic effect of GA‑A on human breast cancer was investigated and the pro‑apoptotic function of Janus kinase (JAK)2 and signal transducer and activator of transcription (STAT)3 on the function of GA‑A was revealed. GA‑A treatment inhibited the invasion of MDA‑MB‑231 cells. In addition, GA‑A exhibited significant antitumor activity by enhancing the apoptotic index and reactive oxygen species production. In the present study, GA‑A was identified to directly inhibit JAK2 phosphorylation and STAT3 downstream activation. In addition, GA‑A suppressed STAT3 target gene expression, including B cell lymphoma‑extra‑large and Myeloid cell leukemia 1, resulting in elevated levels of proteins associated with mitochondrial apoptosis in addition to inhibitors of cyclin‑dependent kinase. GA‑A, in combination with AG490, a JAK2/STAT3 inhibitor, further decreased MDA‑MB‑231 cell viability. In conclusion, GA‑A treatment inhibited breast cancer cell viability via JAK2/STAT3 downregulation and may regulate associated targets to serve an anti‑MDA‑MB‑231 role, including mitochondrial apoptosis and regulating the expression of cell‑cycle‑associated factors.

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1	Foulkes WD, Smith IE and Reis-Filho JS: Triple-negative breast cancer. N Engl J Med. 363:1938–1948. 2010. View Article : Google Scholar : PubMed/NCBI
2	Sun S, Zhao Y and Xu K: Post-adjuvant chemotherapy for triple-negative breast cancer. Med Hypotheses. 90:74–75. 2016. View Article : Google Scholar : PubMed/NCBI
3	Wang X, Crowe PJ, Goldstein D and Yang JL: STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (review). Int J Oncol. 41:1181–1191. 2012. View Article : Google Scholar : PubMed/NCBI
4	Kim MS, Lee WS, Jeong J, Kim SJ and Jin W: Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in the breast cancer. Oncotarget. 6:40158–40171. 2015. View Article : Google Scholar : PubMed/NCBI
5	Wu L, Guo L, Liang Y, Liu X, Jiang L and Wang L: Curcumin suppresses stem-like traits of lung cancer cells via inhibiting the JAK2/STAT3 signaling pathway. Oncol Rep. 34:3311–3317. 2015. View Article : Google Scholar : PubMed/NCBI
6	Zhao H, Guo Y, Li S, Han R, Ying J, Zhu H, Wang Y, Yin L, Han Y, Sun L, et al: A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway. Oncotarget. 6:31927–31943. 2015. View Article : Google Scholar : PubMed/NCBI
7	Liu X, Wang J, Wang H, Yin G, Liu Y, Lei X and Xiang M: REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop. Cancer Lett. 362:45–60. 2015. View Article : Google Scholar : PubMed/NCBI
8	Wang SW, Hu J, Guo QH, Zhao Y, Cheng JJ, Zhang DS, Fei Q, Li J and Sun YM: AZD1480, a JAK inhibitor, inhibits cell growth and survival of colorectal cancer via modulating the JAK2/STAT3 signaling pathway. Oncol Rep. 32:1991–1998. 2014. View Article : Google Scholar : PubMed/NCBI
9	Jorvig JE and Chakraborty A: Zerumbone inhibits growth of hormone refractory prostate cancer cells by inhibiting JAK2/STAT3 pathway and increases paclitaxel sensitivity. Anticancer Drugs. 26:160–166. 2015. View Article : Google Scholar : PubMed/NCBI
10	Gritsina G, Xiao F, O'Brien SW, Gabbasov R, Maglaty MA, Xu RH, Thapa RJ, Zhou Y, Nicolas E, Litwin S, et al: Targeted blockade of JAK/STAT3 signaling inhibits ovarian carcinoma Growth. Mol Cancer Ther. 14:1035–1047. 2015. View Article : Google Scholar : PubMed/NCBI
11	Judd LM, Menheniott TR, Ling H, Jackson CB, Howlett M, Kalantzis A, Priebe W and Giraud AS: Inhibition of the JAK2/STAT3 pathway reduce gastric cancer growth in vitro and in vivo. PLoS One. 9:e959932014. View Article : Google Scholar : PubMed/NCBI
12	Liu Y, Wang L, Wu Y, Lv C, Li X, Cao X, Yang M, Feng D and Luo Z: Pterostilbene exerts antitumor activity against human osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway. Toxicology. 304:120–131. 2013. View Article : Google Scholar : PubMed/NCBI
13	Ruan W, Wei Y and Popovich DG: Distinct responses of cytotoxic Ganoderma lucidum trierpenoids in human carcinoma cells. Phytother Res. 29:1744–1752. 2015. View Article : Google Scholar : PubMed/NCBI
14	Radwan FF, Hossain A, God JM, Leaphart N, Elvington M, Nagarkatti M, Tomlinson S and Haque A: Reduction of myeloid-derived suppressor cells and lymphoma growth by a natural triterpenoid. J Cell Biochem. 116:102–114. 2015. View Article : Google Scholar : PubMed/NCBI
15	Yao X, Li G, Xu H and Lü C: Inhibition of the JAK-STAT3 signaling pathway by ganoderic acid A enhances chemosensitivity of HepG2 cells to cisplatin. Planta Med. 78:1740–1748. 2012. View Article : Google Scholar : PubMed/NCBI
16	Shao J, Li Z, Jiao G, Sun G and Zhou Z: Ganoderic acid A suppresses proliferation and invasion and induces apoptosis in human osteosarcoma cells. Nan Fang Yi Ke Da Xue Xue Bao. 35:619–624. 2015.(In Chinese). PubMed/NCBI
17	Quintás-Cardama A and Verstovsek S: Molecular pathways: JAK/STAT pathway: Mutations, inhibitors, and resistance. Clin Cancer Res. 19:1933–1940. 2013. View Article : Google Scholar : PubMed/NCBI
18	Buchert M, Burns CJ and Ernst M: Targeting JAK kinase in solid tumors: Emerging opportunities and challenges. Oncogene. 35:939–951. 2016. View Article : Google Scholar : PubMed/NCBI
19	Khanna P, Chua PJ, Bay BH and Baeg GH: The JAK/STAT signaling cascade in gastric carcinoma (Review). Int J Oncol. 47:1617–1626. 2015. View Article : Google Scholar : PubMed/NCBI
20	O'Shea JJ, Holland SM and Staudt LM: JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 368:161–170. 2013. View Article : Google Scholar : PubMed/NCBI
21	Bowman T, Garcia R, Turkson J and Jove R: STATs in oncogenesis. Oncogene. 19:2474–2488. 2000. View Article : Google Scholar : PubMed/NCBI
22	Yu H, Pardoll D and Jove R: STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI
23	Walker SR, Xiang M and Frank DA: STAT3 activity and function in cancer: Modulation by STAT5 and miR-146b. Cancers (Basel). 6:958–968. 2014. View Article : Google Scholar : PubMed/NCBI
24	He G and Karin M: NF-κB and STAT3-key players in liver inflammation and cancer. Cell Res. 21:159–168. 2011. View Article : Google Scholar : PubMed/NCBI
25	Frank DA: STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett. 251:199–210. 2007. View Article : Google Scholar : PubMed/NCBI
26	Schroeder A, Herrmann A, Cherryholmes G, Kowolik C, Buettner R, Pal S, Yu H, Müller-Newen G and Jove R: Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res. 74:1227–1237. 2014. View Article : Google Scholar : PubMed/NCBI
27	Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C and Lin J: STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 71:7226–7237. 2011. View Article : Google Scholar : PubMed/NCBI
28	Kim DY, Cha ST, Ahn DH, Kang HY, Kwon CI, Ko KH, Hwang SG, Park PW, Rim KS and Hong SP: STAT3 expression in gastric cancer indicates a poor prognosis. J Gastroenterol Hepatol. 24:646–651. 2009. View Article : Google Scholar : PubMed/NCBI
29	Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL and Xie K: Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 22:319–329. 2003. View Article : Google Scholar : PubMed/NCBI
30	Kamran MZ, Patil P and Gude RP: Role of STAT3 in cancer metastasis and translational advance. Biomed Res Int. 2013:4218212013. View Article : Google Scholar : PubMed/NCBI
31	Li Y, Yang F, Zheng W, Hu M, Wang J, Ma S, Deng Y, Luo Y, Ye T and Yin W: Punica granatum (pomegranate) leaves extract induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in non-small cell lung cancer in vitro. Biomed Pharmacother. 80:227–235. 2016. View Article : Google Scholar : PubMed/NCBI
32	Li X, Zhang Q, Cai L, Wang Y, Wang Q, Huang X, Fu S, Bai J, Liu J, Zhang G and Qi J: Inhibitor of growth 4 induces apoptosis in human lung adenocarcinoma cell line A549 via Bcl-2 family proteins and mitochondria apoptosis pathway. J Cancer Res Clin Oncol. 135:829–835. 2009. View Article : Google Scholar : PubMed/NCBI
33	Su JC, Lin KL, Chien CM, Chuang PW, Chang LS and Lin SR: Concomitant inactivation of the epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt and Janus tyrosine kinase 2/signal transducer and activator of transcription 3 signalling pathways in cardiotoxin III-treated A549 cells. Clin Exp Pharmacol Physiol. 37:833–840. 2010.PubMed/NCBI
34	Du W, Hong J, Wang YC, Zhang YJ, Wang P, Su WY, Lin YW, Lu R, Zou WP, Xiong H and Fang JY: Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway. J Cell Mol Med. 16:1878–1888. 2012. View Article : Google Scholar : PubMed/NCBI
35	Bhardwaj M, Kim NH, Paul S, Jakhar R, Han J and Kang SC: 5-Hydroxy-7-methoxyflavone triggers mitochondrial-associated cell death via reactive oxygen species signaling in human colon carcinoma cells. PLoS One. 11:e01545252016. View Article : Google Scholar : PubMed/NCBI
36	Zhang F, Wang Z, Yuan J, Wei X, Tian R and Niu R: RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway. Breast Cancer Res Treat. 153:263–275. 2015. View Article : Google Scholar : PubMed/NCBI
37	Cai Q, Lin J, Wei L, Zhang L, Wang L, Zhan Y, Zeng J, Xu W, Shen A, Hong Z and Peng J: Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of STAT3 signaling pathway. Int J Mol Sci. 13:6117–6128. 2012. View Article : Google Scholar : PubMed/NCBI
38	Zhou Y, Zeng Z, Zhang W, Xiong W, Wu M, Tan Y, Yi W, Xiao L, Li X, Huang C, et al: Lactotransferrin: A candidate tumor suppressor-deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen-activated protein kinase pathway. Int J Cancer. 123:2065–2072. 2008. View Article : Google Scholar : PubMed/NCBI
39	Sai K, Wang S, Balasubramaniyan V, Conrad C, Lang FF, Aldape K, Szymanski S, Fokt I, Dasgupta A, Madden T, et al: Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway. J Neurooncol. 107:487–501. 2012. View Article : Google Scholar : PubMed/NCBI