Protein kinase C ζ regulates survivin expression and inhibits apoptosis in colon cancer

Umemori,Yoshifumi; Kuribayashi,Kageaki; Nirasawa,Shinya; Kondoh,Takashi; Tanaka,Maki; Kobayashi,Daisuke; Watanabe,Naoki

doi:10.3892/ijo.2014.2489

Protein kinase C ζ regulates survivin expression and inhibits apoptosis in colon cancer

Authors:
- Yoshifumi Umemori
- Kageaki Kuribayashi
- Shinya Nirasawa
- Takashi Kondoh
- Maki Tanaka
- Daisuke Kobayashi
- Naoki Watanabe
View Affiliations

Affiliations: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
Published online on: June 10, 2014 https://doi.org/10.3892/ijo.2014.2489
Pages: 1043-1050

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

The phosphatidylinositol 3-kinase pathway transduces cell survival signals in different malignancies. Protein kinase C ζ (PKCζ) is one of the molecules involved in this pathway. In this study, we investigated the role of PKCζ in apoptosis. Short interfering RNA against PKCζ (siPKCζ) sensitized HCT116 and SW480 colon cancer cells to TRAIL‑induced apoptosis. Among anti-apoptotic proteins, survivin protein and mRNA expression levels decreased after siPKCζ transfection while protein half-life did not change. The expression levels of survivin and PKCζ were correlated in 18 colon cancer specimens (r=0.72, P=3.01x10‑4). Chemosensitivity to 5-FU was enhanced by siPKCζ in HCT116 and SW480 cells. These results indicate that PKCζ regulates survivin expression levels and inhibits apoptosis in colon cancer cells. This study provides a rationale for targeting PKCζ in combination with chemotherapy for colon cancer treatment.

View Figures

View References

1	Vivanco I and Sawyers CL: The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
2	Cully M, You H, Levine AJ and Mak TW: Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 6:184–192. 2006. View Article : Google Scholar : PubMed/NCBI
3	Karakas B, Bachman KE and Park BH: Mutation of the PIK3CA oncogene in human cancers. Br J Cancer. 94:455–459. 2006. View Article : Google Scholar : PubMed/NCBI
4	Liaw D, Marsh DJ, Li J, et al: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 16:64–67. 1997. View Article : Google Scholar : PubMed/NCBI
5	Castellano E and Downward J: Role of RAS in the regulation of PI 3-kinase. Curr Top Microbiol Immunol. 346:143–169. 2010.PubMed/NCBI
6	Chan SK, Gullick WJ and Hill ME: Mutations of the epidermal growth factor receptor in non-small cell lung cancer - search and destroy. Eur J Cancer. 42:17–23. 2006. View Article : Google Scholar : PubMed/NCBI
7	Ross JS and Fletcher JA: The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells. 16:413–428. 1998. View Article : Google Scholar
8	Quintas-Cardama A and Cortes J: Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 113:1619–1630. 2009. View Article : Google Scholar : PubMed/NCBI
9	Alessi DR, James SR, Downes CP, et al: Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 7:261–269. 1997. View Article : Google Scholar
10	Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P and Parker PJ: Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science. 281:2042–2045. 1998.
11	Chou MM, Hou W, Johnson J, et al: Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr Biol. 8:1069–1077. 1998. View Article : Google Scholar : PubMed/NCBI
12	Diaz-Meco MT, Lozano J, Municio MM, et al: Evidence for the in vitro and in vivo interaction of Ras with protein kinase C zeta. J Biol Chem. 269:31706–31710. 1994.PubMed/NCBI
13	Kuribayashi K, Nakamura K, Tanaka M, et al: Essential role of protein kinase C zeta in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP. J Cell Biol. 176:1049–1060. 2007. View Article : Google Scholar : PubMed/NCBI
14	Valkov A, Sorbye SW, Kilvaer TK, et al: The prognostic impact of TGF-beta1, fascin, NF-kappaB and PKC-zeta expression in soft tissue sarcomas. PLoS One. 6:e175072011. View Article : Google Scholar : PubMed/NCBI
15	Yu LR, Lv JQ, Jin LY, et al: Over-expression of protein kinase Cisoforms (alpha, delta, theta and zeta) in squamous cervical cancer. Neoplasma. 58:491–498. 2011.PubMed/NCBI
16	Yao S, Bee A, Brewer D, et al: PRKC-zeta expression promotes the aggressive phenotype of human prostate cancer cells and is a novel target for therapeutic intervention. Genes Cancer. 1:444–464. 2010. View Article : Google Scholar
17	Schonwasser DC, Marais RM, Marshall CJ and Parker PJ: Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol. 18:790–798. 1998.
18	Cohen EE, Lingen MW, Zhu B, et al: Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase. Cancer Res. 66:6296–6303. 2006. View Article : Google Scholar : PubMed/NCBI
19	Sun R, Gao P, Chen L, et al: Protein kinase C zeta is required for epidermal growth factor-induced chemotaxis of human breast cancer cells. Cancer Res. 65:1433–1441. 2005. View Article : Google Scholar : PubMed/NCBI
20	Datta K, Li J, Bhattacharya R, Gasparian L, Wang E and Mukhopadhyay D: Protein kinase C zeta transactivates hypoxia-inducible factor alpha by promoting its association with p300 in renal cancer. Cancer Res. 64:456–462. 2004. View Article : Google Scholar : PubMed/NCBI
21	Jhawer M, Goel S, Wilson AJ, et al: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 68:1953–1961. 2008. View Article : Google Scholar
22	Kim SH, Kim K, Kwagh JG, et al: Death induction by recombinant native TRAIL and its prevention by a caspase 9 inhibitor in primary human esophageal epithelial cells. J Biol Chem. 279:40044–40052. 2004. View Article : Google Scholar : PubMed/NCBI
23	Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 343:905–914. 2000. View Article : Google Scholar : PubMed/NCBI
24	de Thonel A, Bettaieb A, Jean C, Laurent G and Quillet-Mary A: Role of protein kinase C zeta isoform in Fas resistance of immature myeloid KG1a leukemic cells. Blood. 98:3770–3777. 2001.PubMed/NCBI
25	Leroy I, de Thonel A, Laurent G and Quillet-Mary A: Protein kinase C zeta associates with death inducing signaling complex and regulates Fas ligand-induced apoptosis. Cell Signal. 17:1149–1157. 2005. View Article : Google Scholar : PubMed/NCBI
26	Xin MG, Gao FQ, May WS, Flagg T and Deng XM: Protein kinase C zeta abrogates the proapoptotic function of bax through phosphorylation. J Biol Chem. 282:21268–21277. 2007. View Article : Google Scholar : PubMed/NCBI
27	Moscat J, Rennert P and Diaz-Meco MT: PKCzeta at the crossroad of NF-kappaB and Jak1/Stat6 signaling pathways. Cell Death Differ. 13:702–711. 2006. View Article : Google Scholar : PubMed/NCBI
28	Asanuma K, Kobayashi D, Furuya D, Tsuji N, Yagihashi A and Watanabe N: A role for survivin in radioresistance of pancreatic cancer cells. Jpn J Cancer Res. 93:1057–1062. 2002. View Article : Google Scholar : PubMed/NCBI
29	Nakamura M, Tsuji N, Asanuma K, et al: Survivin as a predictor of cis-diamminedichloroplatinum sensitivity in gastric cancer patients. Cancer Sci. 95:44–51. 2004. View Article : Google Scholar : PubMed/NCBI
30	Ceballos-Cancino G, Espinosa M, Maldonado V and Melendez-Zajgla J: Regulation of mitochondrial Smac/DIABLO-selective release by survivin. Oncogene. 26:7569–7575. 2007. View Article : Google Scholar : PubMed/NCBI
31	Dohi T, Okada K, Xia F, et al: An IAP-IAP complex inhibits apoptosis. J Biol Chem. 279:34087–34090. 2004. View Article : Google Scholar : PubMed/NCBI
32	Dohi T, Xia F and Altieri DC: Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection. Mol Cell. 27:17–28. 2007. View Article : Google Scholar : PubMed/NCBI
33	Song Z, Yao X and Wu M: Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J Biol Chem. 278:23130–23140. 2003. View Article : Google Scholar
34	Altieri DC: Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer. 8:61–70. 2008. View Article : Google Scholar : PubMed/NCBI
35	Ye Q, Cai W, Zheng Y, Evers BM and She QB: ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene. Apr 29–2013.(Epub ahead of print). View Article : Google Scholar
36	Diaz-Meco MT and Moscat J: The atypical PKCs in inflammation: NF-kappaB and beyond. Immunol Rev. 246:154–167. 2012. View Article : Google Scholar : PubMed/NCBI
37	Lee WC, Berry R, Hohenstein P and Davies J: siRNA as a tool for investigating organogenesis: The pitfalls and the promises. Organogenesis. 4:176–181. 2008. View Article : Google Scholar : PubMed/NCBI
38	Zhao J, Tenev T, Martins LM, Downward J and Lemoine NR: The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner. J Cell Sci. 113:4363–4371. 2000.PubMed/NCBI
39	Abdulghani J and El-Deiry WS: TRAIL receptor signaling and therapeutics. Expert Opin Ther Targets. 14:1091–1108. 2010. View Article : Google Scholar
40	Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A and Ford HL: On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene. 32:1341–1350. 2013. View Article : Google Scholar : PubMed/NCBI
41	Reyland ME: Protein kinase C isoforms: multi-functional regulators of cell life and death. Front Biosci. 14:2386–2399. 2009. View Article : Google Scholar : PubMed/NCBI
42	Murray NR, Kalari KR and Fields AP: Protein kinase Ciota expression and oncogenic signaling mechanisms in cancer. J Cell Physiol. 226:879–887. 2011. View Article : Google Scholar : PubMed/NCBI
43	Kuribayashi K and El-Deiry WS: Regulation of programmed cell death by the p53 pathway. Adv Exp Med Biol. 615:201–221. 2008. View Article : Google Scholar : PubMed/NCBI
44	Kuribayashi K, Finnberg N, Jeffers JR, Zambetti GP and El-Deiry WS: The relative contribution of pro-apoptotic p53-target genes in the triggering of apoptosis following DNA damage in vitro and in vivo. Cell Cycle. 10:2380–2389. 2011. View Article : Google Scholar : PubMed/NCBI
45	Kuribayashi K, Mayes PA and El-Deiry WS: What are caspases 3 and 7 doing upstream of the mitochondria? Cancer Biol Ther. 5:763–765. 2006. View Article : Google Scholar : PubMed/NCBI