Triptolide induces protective autophagy and apoptosis in human cervical cancer cells by downregulating Akt/mTOR activation

Qin,Guangyi; Li,Ping; Xue,Zhuowei

doi:10.3892/ol.2018.9074

Triptolide induces protective autophagy and apoptosis in human cervical cancer cells by downregulating Akt/mTOR activation

Authors:
- Guangyi Qin
- Ping Li
- Zhuowei Xue
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Affiliations: Department of Obstetrics and Gynaecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
Published online on: July 4, 2018 https://doi.org/10.3892/ol.2018.9074
Pages: 3929-3934

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Abstract

Triptolide exhibits immunosuppressive, anti‑inflammatory, antifertility and antineoplastic functions. However, the anticancer effect of triptolide on cervical cancer and the underlying mechanism remains to be fully understood. The present study assessed the mechanisms underlying the effect of triptolide on the viability and apoptosis of human cervical cancer cells. SiHa cells were treated with 12.5‑100.0 nM triptolide for 12, 24 or 48 h. The present study demonstrated that triptolide inhibited viability and induced apoptosis in SiHa cells time‑ and dose‑dependently. Furthermore, treatment with triptolide promoted autophagy and activated microtubule associated protein 1 light chain 3 α expression in SiHa cells. Triptolide treatment suppressed the expression of phosphorylated (p)‑protein kinase B (Akt), p‑mechanistic target of rapamycin (mTOR), and p‑p70S6K, activated the expression of p‑p38, mitogen‑activated protein kinase (MAPK) and p53 and inhibited the expression of p‑forkhead box O3 (Foxo3a) in SiHa cells. These results suggested that triptolide induces protective autophagy, suppresses cell viability and promotes apoptosis in human cervical cancer cells by inducing the autophagy‑targeting phosphoinositide 3‑kinase/Akt/mTOR, p38, MAPK, p53 and Foxo3a pathways.

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1	Li JM, Shao JL, Zeng WJ and Liang RB: General/epidural anesthesia in combination preserves NK cell activity and affects cytokine response in cervical carcinoma patients undergoing radical resection: A cohort prospective study. Eur J Gynaecol Oncol. 36:703–707. 2015.PubMed/NCBI
2	Herrero R, Quint W, Hildesheim A, Gonzalez P, Struijk L, Katki HA, Porras C, Schiffman M, Rodriguez AC, Solomon D, et al: Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 8:e683292013. View Article : Google Scholar : PubMed/NCBI
3	Frumovitz M, Querleu D, Gil-Moreno A, Morice P, Jhingran A, Munsell MF, Macapinlac HA, Leblanc E, Martinez A and Ramirez PT: Lymphadenectomy in locally advanced cervical cancer study (LiLACS): Phase III clinical trial comparing surgical with radiologic staging in patients with stages IB2-IVA cervical cancer. J Minim Invasive Gynecol. 21:3–8. 2014. View Article : Google Scholar : PubMed/NCBI
4	Xu Y, Yu H, Qin H, Kang J, Yu C, Zhong J, Su J, Li H and Sun L: Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells. Cancer Lett. 314:232–243. 2012. View Article : Google Scholar : PubMed/NCBI
5	Chen TC, Hung YC, Lin TY, Chang HW, Chiang IP, Chen YY and Chow KC: Human papillomavirus infection and expression of ATPase family AAA domain containing 3A, a novel anti-autophagy factor, in uterine cervical cancer. Int J Mol Med. 28:689–696. 2011.PubMed/NCBI
6	Xu L, Liu JH, Zhang J, Zhang N and Wang ZH: Blockade of autophagy aggravates endoplasmic reticulum stress and improves Paclitaxel cytotoxicity in human cervical cancer cells. Cancer Res Treat. 47:313–321. 2015. View Article : Google Scholar : PubMed/NCBI
7	Liu Q, Luo XY, Jiang H, Yang MH, Yuan GH, Tang Z and Wang H: Hydroxychloroquine facilitates autophagosome formation but not degradation to suppress the proliferation of cervical cancer SiHa cells. Oncol Lett. 7:1057–1062. 2014. View Article : Google Scholar : PubMed/NCBI
8	Kim A, Yim NH and Ma JY: Samsoeum, a traditional herbal medicine, elicits apoptotic and autophagic cell death by inhibiting Akt/mTOR and activating the JNK pathway in cancer cells. BMC Complement Altern Med. 13:2332013. View Article : Google Scholar : PubMed/NCBI
9	Li Z, Ji X, Wang W, Liu J, Liang X, Wu H, Liu J, Eggert US, Liu Q and Zhang X: Ammonia Induces autophagy through dopamine receptor D3 and MTOR. PLoS One. 11:e01535262016. View Article : Google Scholar : PubMed/NCBI
10	Belzile JP, Sabalza M, Craig M, Clark E, Morello CS and Spector DH: Trehalose, an mTOR-independent inducer of autophagy, inhibits human cytomegalovirus infection in multiple cell types. J Virol. 90:1259–1277. 2015. View Article : Google Scholar : PubMed/NCBI
11	Wang X, Feng Z, Li J, Chen L and Tang W: High glucose induces autophagy of MC3T3-E1 cells via ROS-AKT-mTOR axis. Mol Cell Endocrinol. 429:62–72. 2016. View Article : Google Scholar : PubMed/NCBI
12	Lv S, Xu QY, Sun EC, Zhang JK and Wu DL: Dissection and integration of the autophagy signaling network initiated by bluetongue virus infection: Crucial candidates ERK1/2, Akt and AMPK. Sci Rep. 6:231302016. View Article : Google Scholar : PubMed/NCBI
13	Park SJ, Ryu J, Kim IH, Choi YH and Nam TJ: Activation of the mTOR signaling pathway in breast cancer MCF7 cells by a peptide derived from porphyra yezoensis. Oncol Rep. 33:19–24. 2015. View Article : Google Scholar : PubMed/NCBI
14	Hu G, Gong X, Wang L, Liu M, Liu Y, Fu X, Wang W, Zhang T and Wang X: Triptolide promotes the clearance of α-synuclein by enhancing autophagy in neuronal cells. Mol Neurobiol. 54:2361–2372. 2017. View Article : Google Scholar : PubMed/NCBI
15	Ziaei S and Halaby R: Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review. Avicenna J Phytomed. 6:149–164. 2016.PubMed/NCBI
16	Zhu W, Hu H, Qiu P and Yan G: Triptolide induces apoptosis in human anaplastic thyroid carcinoma cells by a p53-independent but NF-kappaB-related mechanism. Oncol Rep. 22:1397–1401. 2009.PubMed/NCBI
17	Jiang XH, Wong BC, Lin MC, Zhu GH, Kung HF, Jiang SH, Yang D and Lam SK: Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene. 20:8009–8018. 2001. View Article : Google Scholar : PubMed/NCBI
18	Verhoef VM, van Kemenade FJ, Rozendaal L, Heideman DA, Bosgraaf RP, Hesselink AT, Melchers WJ, Massuger LF, Bekkers RL, Steenbergen RD, et al: Follow-up of high-risk HPV positive women by combined cytology and bi-marker CADM1/MAL methylation analysis on cervical scrapes. Gynecol Oncol. 137:55–59. 2015. View Article : Google Scholar : PubMed/NCBI
19	Rangwala R, Chang YC, Hu J, Algazy KM, Evans TL, Fecher LA, Schuchter LM, Torigian DA, Panosian JT, Troxel AB, et al: Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy. 10:1391–1402. 2014. View Article : Google Scholar : PubMed/NCBI
20	Hogdal N, Juhl C, Aadahl M and Gluud C: Early preventive exercises versus usual care does not seem to reduce trismus in patients treated with radiotherapy for cancer in the oral cavity or oropharynx: A randomised clinical trial. Acta Oncol. 54:80–87. 2015. View Article : Google Scholar : PubMed/NCBI
21	Wang J, Ou J, Guo Y, Dai T, Li X, Liu J, Xia M, Liu L and He M: TBLR1 is a novel prognostic marker and promotes epithelial-mesenchymal transition in cervical cancer. Br J Cancer. 111:112–124. 2014. View Article : Google Scholar : PubMed/NCBI
22	Wei B, Huang Q, Huang S, Mai W and Zhong X: Trichosanthin-induced autophagy in gastric cancer cell MKN-45 is dependent on reactive oxygen species (ROS) and NF-kB/p53 pathway. J Pharmacol Sci. 131:77–83. 2016. View Article : Google Scholar : PubMed/NCBI
23	Leisching G, Loos B, Botha M and Engelbrecht AM: A nontoxic concentration of cisplatin induces autophagy in cervical cancer: Selective cancer cell death with autophagy inhibition as an adjuvant treatment. Int J Gynecol Cancer. 25:380–388. 2015. View Article : Google Scholar : PubMed/NCBI
24	Florey O, Gammoh N, Kim SE, Jiang X and Overholtzer M: V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation. Autophagy. 11:88–99. 2015. View Article : Google Scholar : PubMed/NCBI
25	Duan J, Yu Y, Yu Y, Li Y, Wang J, Geng W, Jiang L, Li Q, Zhou X and Sun Z: Silica nanoparticles induce autophagy and endothelial dysfunction via the PI3K/Akt/mTOR signaling pathway. Int J Nanomedicine. 9:5131–5141. 2014. View Article : Google Scholar : PubMed/NCBI
26	Mujumdar N, Mackenzie TN, Dudeja V, Chugh R, Antonoff MB, Borja-Cacho D, Sangwan V, Dawra R, Vickers SM and Saluja AK: Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways. Gastroenterology. 139:598–608. 2010. View Article : Google Scholar : PubMed/NCBI
27	Yu CC, Huang HB, Hung SK, Liao HF, Lee CC, Lin HY, Li SC, Ho HC, Hung CL and Su YC: AZD2014 radiosensitizes oral squamous cell carcinoma by inhibiting AKT/mTOR axis and inducing G1/G2/M cell cycle arrest. PLoS One. 11:e01519422016. View Article : Google Scholar : PubMed/NCBI
28	Zhao F, Huang W, Zhang Z, Mao L, Han Y, Yan J and Lei M: Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells. Oncotarget. 7:5366–5382. 2016.PubMed/NCBI
29	Kang EB and Cho JY: Effect of treadmill exercise on PI3K/AKT/mTOR, autophagy, and Tau hyperphosphorylation in the cerebral cortex of NSE/htau23 transgenic mice. J Exerc Nutrition Biochem. 19:199–209. 2015. View Article : Google Scholar : PubMed/NCBI
30	Baena M, Sanguesa G, Hutter N, Sánchez RM, Roglans N, Laguna JC and Alegret M: Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress. Biochim Biophys Acta. 1851:107–116. 2015. View Article : Google Scholar : PubMed/NCBI
31	Chen L, Jiang Z, Ma H, Ning L, Chen H, Li L and Qi H: Volatile oil of acori graminei Rhizoma-induced apoptosis and autophagy are dependent on p53 status in human glioma cells. Sci Rep. 6:211482016. View Article : Google Scholar : PubMed/NCBI
32	Li JP, Yang YX, Liu QL, Pan ST, He ZX, Zhang X, Yang T, Chen XW, Wang D, Qiu JX and Zhou SF: The investigational Aurora kinase A inhibitor alisertib (MLN8237) induces cell cycle G2/M arrest, apoptosis, and autophagy via p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells. Drug Des Devel Ther. 9:1627–1652. 2015.PubMed/NCBI
33	Xiong J, Su T, Qu Z, Yang Q, Wang Y, Li J and Zhou S: Triptolide has anticancer and chemosensitization effects by down-regulating Akt activation through the MDM2/REST pathway in human breast cancer. Oncotarget. 7:23933–23946. 2016. View Article : Google Scholar : PubMed/NCBI
34	Park SW and Kim YI: Triptolide induces apoptosis of PMA-treated THP-1 cells through activation of caspases, inhibition of NF-kB and activation of MAPKs. Int J Oncol. 43:1169–1175. 2013. View Article : Google Scholar : PubMed/NCBI