β‑elemene induced anticancer effect in bladder cancer through upregulation of PTEN and suppression of AKT phosphorylation

Cai,Bo; Ma,Limin; Nong,Shaojun; Wu,You; Guo,Xin; Pu,Jinxian

doi:10.3892/ol.2018.9401

β‑elemene induced anticancer effect in bladder cancer through upregulation of PTEN and suppression of AKT phosphorylation

Authors:
- Bo Cai
- Limin Ma
- Shaojun Nong
- You Wu
- Xin Guo
- Jinxian Pu
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Affiliations: Department of Urology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Urology, The First Affiliated Hospital of Suzhou University, Suzhou, Jiangsu 215001, P.R. China
Published online on: September 5, 2018 https://doi.org/10.3892/ol.2018.9401
Pages: 6019-6025

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Abstract

Human bladder cancer is one of the most aggressive tumours known and has shown resistance to traditional chemotherapy, which depends heavily on DNA‑damaging drugs. β‑elemene is one of the least cytotoxic antitumor agents that are extracted from Curcuma aromatica salisb and it exhibits antitumor effects in many carcinomas. β‑elemene has attracted the attention of clinicians and scientists worldwide due to its few side effects and limited effect on the bone marrow. However, the antitumor mechanism of β‑elemene remains largely unstudied. In the present study, the expression of the AKT serine/threonine kinase (AKT) signaling pathway in bladder cancer and normal bladder tissue was investigated, and the influence of β‑elemene on bladder cancer cells and the mechanisms involved were assessed. The results showed that phosphatase and tensin homolog deleted on chromosome ten (PTEN) was downregulated and phosphorylated‑AKT (pAKT) was overexpressed in human bladder cancer. β‑elemene significantly suppressed the viability of bladder cancer cells, while leaving normal bladder cells unaffected. In addition, there was an increased number of apoptotic bladder cancer cells following β‑elemene treatment, and a significant reduction in cell invasion and migration. Subsequent western blot analyses revealed that bladder cancer cells treated with β‑elemene had increased PTEN expression and decreased expression of pAKT. Taken together, these results suggest that β‑elemene has an antitumor effect in bladder cancer cells through the upregulation of PTEN and suppression of AKT phosphorylation.

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1	Kaprin AD, Kostin AA, Rapoport LM, Tsarichenko DG, Bernikov AN, Vorob'ev NV and Golovashchenko MP: Cancer of urinary bladder. Urologiia. 6 Suppl:S64–S88. 2016.(In Russian).
2	Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, Guo CC, Lotan Y and Kassouf W: Bladder cancer. Lancet. 388:2796–2810. 2016. View Article : Google Scholar : PubMed/NCBI
3	Lan Y, Liu D and Lin M: Comparison of the combination therapy of bacillus Calmette-Guerin and mitomycin C with the monotherapy for non-muscle-invasive bladder cancer: A meta-analysis. Neoplasma. 63:967–976. 2016. View Article : Google Scholar : PubMed/NCBI
4	Krasnow RE, Drumm M, Roberts HJ, Niemierko A, Wu CL, Wu S, Zhang J, Heney NM, Wszolek MF, Blute ML, et al: Clinical outcomes of patients with histologic variants of urothelial cancer treated with trimodality bladder-sparing therapy. Eur Urol. 72:54–60. 2017. View Article : Google Scholar : PubMed/NCBI
5	Ding XF, Shen M, Xu LY, Dong JH and Chen G: 13,14-bis(cis-3,5-dimethyl-1-piperazinyl)-β-elemene, a novel β-elemene derivative, shows potent antitumor activities via inhibition of mTOR in human breast cancer cells. Oncol Lett. 5:1554–1558. 2013. View Article : Google Scholar : PubMed/NCBI
6	Hu Z, Wu H, Li Y, Hou Q, Wang Y, Li S, Xia B and Wu S: β-Elemene inhibits the proliferation of esophageal squamous cell carcinoma by regulating long noncoding RNA-mediated inhibition of hTERT expression. Anticancer Drugs. 26:531–539. 2015. View Article : Google Scholar : PubMed/NCBI
7	Zou S, Wang C, Cui Z, Guo P, Meng Q, Shi X, Gao Y, Yang G and Han Z: β-Elemene induces apoptosis of human rheumatoid arthritis fibroblast-like synoviocytes via reactive oxygen species-dependent activation of p38 mitogen-activated protein kinase. Pharmacol Rep. 68:7–11. 2016. View Article : Google Scholar : PubMed/NCBI
8	Chen JC, Duan WL, Bai RR, Yao HQ, Wu XM, Shang J and Xu JY: Synthesis of 13-β-elemene ester derivatives and evaluation of their antioxidant activity in human umbilical vein endothelial cells. Chin J Nat Med. 13:618–627. 2015.PubMed/NCBI
9	Hong L, Zeng Y and Yang D: Inhibitory effect of β-elemene on human airway granulation tissue in vivo and in vitro. Respiration. 92:329–338. 2016. View Article : Google Scholar : PubMed/NCBI
10	Bai H, Li H, Li W, Gui T, Yang J, Cao D and Shen K: The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget. 6:25520–25532. 2015. View Article : Google Scholar : PubMed/NCBI
11	Olasz J, Doleschall Z, Dunai Z, Pazsitka A and Csuka O: PI3K/AKT pathway activation and therapeutic consequences in breast cancer. Magy Onkol. 59:346–351. 2015.(In Hungarian). PubMed/NCBI
12	Brotelle T and Bay JO: PI3K-AKT-mTOR pathway: Description, therapeutic development, resistance, predictive/prognostic biomarkers and therapeutic applications for cancer. Bull Cancer. 103:18–29. 2016.(In French). View Article : Google Scholar : PubMed/NCBI
13	Rana C, Piplani H, Vaish V, Nehru B and Sanyal SN: Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer. Mol Cell Biochem. 402:225–241. 2015. View Article : Google Scholar : PubMed/NCBI
14	Chun SH, Jung CK, Won HS, Kang JH, Kim YS and Kim MS: Divergence of P53, PTEN, PI3K, Akt and mTOR expression in tonsillar cancer. Head Neck. 37:636–643. 2015. View Article : Google Scholar : PubMed/NCBI
15	Lim HJ, Crowe P and Yang JL: Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. J Cancer Res Clin Oncol. 141:671–689. 2015. View Article : Google Scholar : PubMed/NCBI
16	Chin CC, Li JM, Lee KF, Huang YC, Wang KC, Lai HC, Cheng CC, Kuo YH and Shi CS: Selective β2-AR blockage suppresses colorectal cancer growth through regulation of EGFR-Akt/ERK1/2 signaling, G1-phase arrest, and apoptosis. J Cell Physiol. 231:459–472. 2016. View Article : Google Scholar : PubMed/NCBI
17	Zhu Y, Dai B, Zhang H, Shi G, Shen Y and Ye D: Long non-coding RNA LOC572558 inhibits bladder cancer cell proliferation and tumor growth by regulating the AKT-MDM2-p53 signaling axis. Cancer Lett. 380:369–374. 2016. View Article : Google Scholar : PubMed/NCBI
18	Chen J, Wang T, Xu S, Zhang P, Lin A, Wu L, Yao H, Xie W, Zhu Z and Xu J: Discovery of novel antitumor nitric oxide-donating β-elemene hybrids through inhibiting the PI3K/Akt pathway. Eur J Med Chem. 135:414–423. 2017. View Article : Google Scholar : PubMed/NCBI
19	Yu X, Xu M, Li N, Li Z, Li H, Shao S, Zou K and Zou L: β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer. Biochem Biophys Res Commun. 490:514–520. 2017. View Article : Google Scholar : PubMed/NCBI
20	Mu L, Wang T, Chen Y, Tang X, Yuan Y and Zhao Y: β-Elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway. Int J Oncol. 49:1427–1436. 2016. View Article : Google Scholar : PubMed/NCBI
21	Zhang J, Zhang HD, Yao YF, Zhong SL, Zhao JH and Tang JH: β-elemene reverses chemoresistance of breast cancer cells by reducing resistance transmission via exosomes. Cell Physiol Biochem. 36:2274–2286. 2015. View Article : Google Scholar : PubMed/NCBI
22	Chen J, Wang R, Wang T, Ding Q, Khalil A, Xu S, Lin A, Yao H, Xie W, Zhu Z and Xu J: Antioxidant properties of novel dimers derived from natural β-elemene through inhibiting H₂O₂-induced apoptosis. ACS Med Chem Lett. 8:443–448. 2017. View Article : Google Scholar : PubMed/NCBI
23	Ma C, Zhou W, Yan Z, Qu M and Bu X: β-Elemene treatment of glioblastoma: A single-center retrospective study. Onco Targets Ther. 9:7521–7526. 2016. View Article : Google Scholar : PubMed/NCBI
24	Chen X, Wang Y, Luo H, Luo Z, Zhang T, Yang N, Long X, Xie H, Qiu W, Zhang B, Ding J and Yang L: β-elemene acts as an antitumor factor and downregulates the expression of survivin, Bcl-xL and Mta-1. Mol Med Rep. 6:989–995. 2012.PubMed/NCBI
25	Lu X, Wang Y, Luo H, Qiu W, Han H and Chen X: β-elemene inhibits the proliferation of T24 bladder carcinoma cells through upregulation of the expression of Smad4. Mol Med Rep. 7:513–518. 2013. View Article : Google Scholar : PubMed/NCBI
26	Tanaka M and Grossman HB: In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin. Gene Ther. 10:1636–1642. 2003. View Article : Google Scholar : PubMed/NCBI
27	Lin C, Tsai SC, Tseng MT, Peng SF, Kuo SC, Lin MW, Hsu YM, Lee MR, Amagaya S, Huang WW, et al: AKT serine/threonine protein kinase modulates baicalin-triggered autophagy in human bladder cancer T24 cells. Int J Oncol. 42:993–1000. 2013. View Article : Google Scholar : PubMed/NCBI
28	Zhao B and Li X: Altholactone induces reactive oxygen species-mediated apoptosis in bladder cancer T24 cells through mitochondrial dysfunction, MAPK-p38 activation and Akt suppression. Oncol Rep. 31:2769–2775. 2014. View Article : Google Scholar : PubMed/NCBI