Involvement of the phosphoinositide 3‑kinase/Akt pathway in apoptosis induced by capsaicin in the human pancreatic cancer cell line PANC-1

Zhang,Jian-Hong; Lai,Fu-Ji; Chen,Hui; Luo,Jiang; Zhang,Ri-Yuan; Bu,He‑Qi; Wang,Zhao-Hong; Lin,Hong-Hai; Lin,Sheng-Zhang

doi:10.3892/ol.2012.991

Involvement of the phosphoinositide 3‑kinase/Akt pathway in apoptosis induced by capsaicin in the human pancreatic cancer cell line PANC-1

Authors:
- Jian-Hong Zhang
- Fu-Ji Lai
- Hui Chen
- Jiang Luo
- Ri-Yuan Zhang
- He‑Qi Bu
- Zhao-Hong Wang
- Hong-Hai Lin
- Sheng-Zhang Lin
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Affiliations: Department of Hepatobiliary-Pancreatic Surgery, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325027, P.R. China
Published online on: October 24, 2012 https://doi.org/10.3892/ol.2012.991
Pages: 43-48

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Abstract

Capsaicin, one of the major pungent ingredients found in red peppers, has been recently demonstrated to induce apoptosis in various malignant cell lines through an unclear mechanism. In this study, the effect of capsaicin on proliferation and apoptosis in the human pancreatic cancer cell line PANC‑1 and its possible mechanism(s) of action were investigated. The results of a Cell Counting Kit-8 (CCK‑8) assay revealed that capsaicin significantly decreased the viability of PANC‑1 cells in a dose-dependent manner. Capsaicin induced G0/G1 phase cell cycle arrest and apoptosis in PANC‑1 cells as demonstrated by a flow cytometric assessment. Caspase‑3 expression at both the protein and mRNA level was promoted following capsaicin treatment. Furthermore, we revealed that phospho‑PI3 Kinase p85 (Tyr458) and phospho‑Akt (Ser473) in PANC‑1 cells were downregulated in response to capsaicin. Moreover, capsaicin gavage significantly inhibited the growth of pancreatic cancer PANC‑1 cell xenografts in athymic nude mice. An increased number of TUNEL‑positive cells and cleaved caspase‑3 were observed in capsaicin-treated mice. In vivo, capsaicin downregulated the expression of phospho‑PI3 Kinase p85 (Tyr458) and phospho‑Akt (Ser473). In conclusion, we have demonstrated that capsaicin is an inhibitor of growth of PANC‑1 cells, and downregulation of the phosphoinositide 3‑kinase/Akt pathway may be involved in capsaicin-induced apoptosis in vitro and in vivo.

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1	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar
2	Raimondi S, Maisonneuve P and Lowenfels AB: Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 6:699–708. 2009. View Article : Google Scholar : PubMed/NCBI
3	Wang L, Yang GH, Lu XH, Huang ZJ and Li H: Pancreatic cancer mortality in China (1991–2000). World J Gastroenterol. 9:1819–1823. 2003.
4	Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar
5	Saif MW: Pancreatic neoplasm in 2011: an update. JOP. 12:316–321. 2011.PubMed/NCBI
6	Stathis A and Moore MJ: Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 7:163–172. 2010. View Article : Google Scholar : PubMed/NCBI
7	Arends JJ, Sleeboom HP, Leys MB, et al: A phase II study of raltitrexed and gemcitabine in patients with advanced pancreatic carcinoma. Br J Cancer. 92:445–448. 2005.PubMed/NCBI
8	Liu P, Cheng H, Roberts TM and Zhao JJ: Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 8:627–644. 2009. View Article : Google Scholar : PubMed/NCBI
9	Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
10	Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:231–241. 1997. View Article : Google Scholar : PubMed/NCBI
11	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and Gonzalez-Baron M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004.PubMed/NCBI
12	Bondar VM, Sweeney-Gotsch B, Andreeff M, Mills GB and McConkey DJ: Inhibition of the phosphatidylinositol 3′-kinase-AKT pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo. Mol Cancer Ther. 1:989–997. 2002.
13	Roy SK, Srivastava RK and Shankar S: Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal. 5:102010. View Article : Google Scholar : PubMed/NCBI
14	Surh YJ: More than spice: capsaicin in hot chili peppers makes tumor cells commit suicide. J Natl Cancer Inst. 94:1263–1265. 2002. View Article : Google Scholar : PubMed/NCBI
15	Surh YJ, Lee E and Lee JM: Chemoprotective properties of some pungent ingredients present in red pepper and ginger. Mutat Res. 402:259–267. 1998. View Article : Google Scholar : PubMed/NCBI
16	Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD and Julius D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 389:816–824. 1997. View Article : Google Scholar
17	Hartel M, di Mola FF, Selvaggi F, et al: Vanilloids in pancreatic cancer: potential for chemotherapy and pain management. Gut. 55:519–528. 2006. View Article : Google Scholar : PubMed/NCBI
18	Pramanik KC, Boreddy SR and Srivastava SK: Role of mitochondrial electron transport chain complexes in capsaicin mediated oxidative stress leading to apoptosis in pancreatic cancer cells. PLoS One. 6:e201512011. View Article : Google Scholar
19	Amantini C, Ballarini P, Caprodossi S, et al: Triggering of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin induces Fas/CD95-mediated apoptosis of urothelial cancer cells in an ATM-dependent manner. Carcinogenesis. 30:1320–1329. 2009. View Article : Google Scholar
20	Kim JY, Kim EH, Kim SU, Kwon TK and Choi KS: Capsaicin sensitizes malignant glioma cells to TRAIL-mediated apoptosis via DR5 upregulation and survivin downregulation. Carcinogenesis. 31:367–375. 2010. View Article : Google Scholar : PubMed/NCBI
21	Ito K, Nakazato T, Yamato K, et al: Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res. 64:1071–1078. 2004. View Article : Google Scholar
22	Sanchez AM, Sanchez MG, Malagarie-Cazenave S, Olea N and Diaz-Laviada I: Induction of apoptosis in prostate tumor PC-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis. 11:89–99. 2006. View Article : Google Scholar : PubMed/NCBI
23	Zhang R, Humphreys I, Sahu RP, Shi Y and Srivastava SK: In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis. 13:1465–1478. 2008. View Article : Google Scholar
24	Shin DH, Kim OH, Jun HS and Kang MK: Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway. Exp Mol Med. 40:486–494. 2008. View Article : Google Scholar : PubMed/NCBI
25	Wei WT, Chen H, Wang ZH, et al: Enhanced antitumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway. Int J Biol Sci. 8:1–14. 2012. View Article : Google Scholar : PubMed/NCBI
26	Wei WT, Chen H, Ni ZL, et al: Antitumor and apoptosis-promoting properties of emodin, an anthraquinone derivative from Rheum officinale Baill, against pancreatic cancer in mice via inhibition of Akt activation. Int J Oncol. 39:1381–1390. 2011.
27	Shanmugam MK, Kannaiyan R and Sethi G: Targeting cell signaling and apoptotic pathways by dietary agents: role in the prevention and treatment of cancer. Nutr Cancer. 63:161–173. 2011. View Article : Google Scholar : PubMed/NCBI
28	Sarkar FH and Li Y: Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res. 66:3347–3350. 2006. View Article : Google Scholar : PubMed/NCBI
29	Degterev A, Boyce M and Yuan J: A decade of caspases. Oncogene. 22:8543–8567. 2003. View Article : Google Scholar : PubMed/NCBI
30	Hamacher R, Schmid RM, Saur D and Schneider G: Apoptotic pathways in pancreatic ductal adenocarcinoma. Mol Cancer. 7:642008. View Article : Google Scholar : PubMed/NCBI
31	Kasibhatla S and Tseng B: Why target apoptosis in cancer treatment? Mol Cancer Ther. 2:573–580. 2003.PubMed/NCBI
32	Hashimoto T, He Z, Ma WY, Schmid PC, Bode AM, Yang CS and Dong Z: Caffeine inhibits cell proliferation by G0/G1 phase arrest in JB6 cells. Cancer Res. 64:3344–3349. 2004. View Article : Google Scholar : PubMed/NCBI
33	Liang J and Slingerland JM: Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2:339–345. 2003. View Article : Google Scholar : PubMed/NCBI