Cryptotanshinone suppresses the proliferation and induces the apoptosis of pancreatic cancer cells via the STAT3 signaling pathway

Ge,Yuqing; Yang,Bo; Chen,Zhe; Cheng,Rubin

doi:10.3892/mmr.2015.4379

Cryptotanshinone suppresses the proliferation and induces the apoptosis of pancreatic cancer cells via the STAT3 signaling pathway

Authors:
- Yuqing Ge
- Bo Yang
- Zhe Chen
- Rubin Cheng
View Affiliations

Affiliations: National Clinical Research Base of Traditional Chinese Medicine, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
Published online on: September 28, 2015 https://doi.org/10.3892/mmr.2015.4379
Pages: 7782-7788

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Pancreatic cancer remains a challenging disease worldwide. Cryptotanshinone (CPT) is one of the active constituents of Salvia miltiorrhiza Bunge and exhibits significant antitumor activities in several human cancer cells. However, the efficacy and molecular mechanism of CPT in pancreatic cancer remains to be elucidated. In the present study, the effect of CPT on the proliferation, apoptosis and cell cycle of human pancreatic cancer cell BxPC‑3 cells was evaluated. The results demonstrated that CPT inhibited proliferation of the BxPC‑3 cells in a concentration‑dependent manner, and significantly induced cell apoptosis and cell cycle arrest. The protein levels of cleaved caspase‑3, caspase‑9 and poly ADP ribose polymerase were upregulated, while the levels of c‑myc, survivin and cyclin D1 were downregulated following treatment with CPT. In addition, CPT decreased the activities of signal transducer and activator of transcription 3 (STAT3) and several upstream regulatory signaling pathways after 24 h. However, CPT only inhibited the phosphorylation of STAT3 Tyr705 within 30 min, without marked effects on the phosphorylation of the other proteins. These results suggested that the inhibition of STAT3 activity by CPT was directly and independent of the upstream regulators in human pancreatic cancer. The present study demonstrated that CPT exerts anticancer effects by inducing apoptosis and cell cycle arrest via inhibition of the STAT3 signaling pathway in human BxPC-3 cells.

View Figures

View References

1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
2	Wang BH, Cao WM, Yu J and Wang XL: Gemcitabine-based concurrent chemoradiotherapy versus chemotherapy alone in patients with locally advanced pancreatic cancer. Asian Pac J Cancer Prev. 13:2129–2132. 2012. View Article : Google Scholar : PubMed/NCBI
3	Matthaios D, Zarogoulidis P, Balgouranidou I, Chatzaki E and Kakolyris S: Molecular pathogenesis of pancreatic cancer and clinical perspectives. Oncology. 81:259–272. 2011. View Article : Google Scholar : PubMed/NCBI
4	Sehara Y, Sawicka K, Hwang JY, Latuszek-Barrantes A, Etgen AM and Zukin RS: Survivin is a transcriptional target of STAT3 critical to estradiol neuroprotection in global ischemia. J Neurosci. 33:12364–12374. 2013. View Article : Google Scholar : PubMed/NCBI
5	Yu H and Jove R: The STATs of cancer-new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI
6	Takezawa K, Okamoto I, Nishio K, Jänne PA and Nakagawa K: Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer. Clin Cancer Res. 17:2140–2148. 2011. View Article : Google Scholar : PubMed/NCBI
7	Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, Yoshimura A, Reindl W, Sipos B, Akira S, et al: Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 19:456–469. 2011. View Article : Google Scholar : PubMed/NCBI
8	Nagaraj NS, Washington MK and Merchant NB: Combined blockade of Src kinase and epidermal growth factor receptor with gemcitabine overcomes STAT3-mediated resistance of inhibition of pancreatic tumor growth. Clin Cancer Res. 17:483–493. 2011. View Article : Google Scholar : PubMed/NCBI
9	Li HD, Huang C, Huang KJ, Wu WD, Jiang T, Cao J, Feng ZZ and Qiu ZJ: STAT3 knockdown reduces pancreatic cancer cell invasiveness and matrix metalloproteinase-7 expression in nude mice. PLoS One. 6:e259412011. View Article : Google Scholar : PubMed/NCBI
10	Huang S and Sinicrope FA: Sorafenib inhibits STAT3 activation to enhance TRAIL-mediated apoptosis in human pancreatic cancer cells. Mol Cancer Ther. 9:742–750. 2010. View Article : Google Scholar : PubMed/NCBI
11	Park IJ, Kim MJ, Park OJ, Choe W, Kang I, Kim SS and Ha J: Cryptotanshinone induces ER stress-mediated apoptosis in HepG2 and MCF7 cells. Apoptosis. 17:248–257. 2012. View Article : Google Scholar
12	Ge Y, Cheng R, Zhou Y, Shen J, Peng L, Xu X, Dai Q, Liu P, Wang H, Ma X, et al: Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E. Mol Cell Biochem. 368:17–25. 2012. View Article : Google Scholar : PubMed/NCBI
13	Chen W, Luo Y, Liu L, Zhou H, Xu B, Han X, Shen T, Liu Z, Lu Y and Huang S: Cryptotanshinone inhibits cancer cell proliferation by suppressing Mammalian target of rapamycin-mediated cyclin D1 expression and Rb phosphorylation. Cancer Prev Res (Phila). 3:1015–1025. 2010. View Article : Google Scholar
14	Shin DS, Kim HN, Shin KD, Yoon YJ, Kim SJ, Han DC and Kwon BM: Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res. 69:193–202. 2009. View Article : Google Scholar : PubMed/NCBI
15	Lu L, Li C, Li D, Wang Y, Zhou C, Shao W, Peng J, You Y, Zhang X and Shen X: Cryptotanshinone inhibits human glioma cell proliferation by suppressing STAT3 signaling. Mol Cell Biochem. 381:273–282. 2013. View Article : Google Scholar : PubMed/NCBI
16	Ge Y, Yang B, Xu X, Dai Q, Chen Z and Cheng R: Cryptotanshinone acts synergistically with imatinib to induce apoptosis of human chronic myeloid leukemia cells. Leuk Lymphoma. 56:730–738. 2015. View Article : Google Scholar
17	Papanikolaou V, Iliopoulos D, Dimou I, Dubos S, Kappas C, Kitsiou-Tzeli S and Tsezou A: Survivin regulation by HER2 through NF-κB and c-myc in irradiated breast cancer cells. J Cell Mol Med. 15:1542–1550. 2011. View Article : Google Scholar
18	Sun M, Liu C, Nadiminty N, Lou W, Zhu Y, Yang J, Evans CP, Zhou Q and Gao AC: Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate. 72:82–89. 2012. View Article : Google Scholar
19	Cao H, LE D and Yang LX: Current status in chemotherapy for advanced pancreatic adenocarcinoma. Anticancer Res. 33:1785–1791. 2013.PubMed/NCBI
20	Schüler S, Diersch S, Hamacher R, Schmid RM, Saur D and Schneider G: SKP2 confers resistance of pancreatic cancer cells towards TRAIL-induced apoptosis. Int J Oncol. 38:219–225. 2011.
21	Pandurangan AK and Esa NM: Signal transducer and activator of transcription 3-a promising target in colitis-associated cancer. Asian Pac J Cancer Prev. 15:551–560. 2014. View Article : Google Scholar
22	Don MJ, Liao JF, Lin LY and Chiou WF: Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. Br J Pharmacol. 151:638–646. 2007. View Article : Google Scholar : PubMed/NCBI
23	Ge YQ, Xu XF, Yang B, Chen Z and Cheng RB: Saponins from Rubus parvifolius L. induce apoptosis in human chronic myeloid leukemia cells through AMPK activation and STAT3 inhibition. Asian Pac J Cancer Prev. 15:5455–5461. 2014. View Article : Google Scholar : PubMed/NCBI
24	Zhang J, Wang P, Ouyang H, Yin J, Liu A, Ma C and Liu L: Targeting cancer-related inflammation: Chinese herbal medicine inhibits epithelial -to- mesenchymal transition in pancreatic cancer. PLoS One. 8:e703342013. View Article : Google Scholar
25	Chen L, Wang HJ, Xie W, Yao Y, Zhang YS and Wang H: Cryptotanshinone inhibits lung tumorigenesis and induces apoptosis in cancer cells in vitro and in vivo. Mol Med Rep. 9:2447–2452. 2014.PubMed/NCBI
26	Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 369:1691–1703. 2013. View Article : Google Scholar : PubMed/NCBI
27	Wang ZH, Chen H, Guo HC, Tong HF, Liu JX, Wei WT, Tan W, Ni ZL, Liu HB and Lin SZ: Enhanced antitumor efficacy by the combination of emodin and gemcitabine against human pancreatic cancer cells via downregulation of the expression of XIAP in vitro and in vivo. Int J Oncol. 39:1123–1131. 2011.PubMed/NCBI
28	Liu A, Chen H, Tong H, Ye S, Qiu M, Wang Z, Tan W, Liu J and Lin S: Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB. Mol Med Rep. 4:221–227. 2011.PubMed/NCBI