IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin

Ma,Xiumei; Bai,Yongrui

doi:10.3892/mmr.2012.1110

IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin

Authors:
- Xiumei Ma
- Yongrui Bai
View Affiliations

Affiliations: Department of Radiation Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, P.R. China
Published online on: September 28, 2012 https://doi.org/10.3892/mmr.2012.1110
Pages: 1433-1437

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

Secretory clusterin (sCLU) is a type of stress-induced, pro-survival glycoprotein elevated in early-stage cancer. It enhances cancer cell survival and is associated with several types of cancer progression. In this study, we measured the PI3K/AKT signaling activity by determining the phosphorylation level of the AKT protein, namely pAKT. A549 human non-small cell lung carcinoma (NSCLC) cells were treated with insulin-like growth factor-1 (IGF-1) for various periods of time. The results showed that IGF-1 activated the PI3K/AKT signaling pathway in the A549 cells in a time-dependent manner. Western blot analysis was performed to determine the expression of sCLU protein in A549 cells treated with IGF-1. IGF-1 elevated the expression of sCLU. To determine whether sCLU is required for the IGF-1 activation of the PI3K/AKT signaling pathway, the A549 cells were treated with IGF-1 and sCLU antisense oligonuleotide (sCLU ASO). sCLU ASO blocked the IGF-1 activation of the PI3K/AKT signaling pathway. These results demonstrate that IGF-1 activates the P13K/AKT signaling pathway via the upregulation of sCLU. The present study implies that this pathway may uncover a new mechanism for cancer progression and reveal new targets for drug development in the treatment of NSCLC.

View Figures

View References

1	O’Sullivan J, Whyte L, Drake J and Tenniswood M: Alterations in the post-translational modification and intracellular trafficking of clusterin in MCF-7 cells during apoptosis. Cell Death Differ. 10:914–927. 2003.PubMed/NCBI
2	Shannan B, Seifert M, Leskov K, et al: Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ. 13:12–19. 2006. View Article : Google Scholar : PubMed/NCBI
3	Tenniswood MP, Guenette RS, Lakins J, Mooibroek M, Wong P and Welsh JE: Active cell death in hormone-dependent tissues. Cancer Metastasis Rev. 11:197–220. 1992. View Article : Google Scholar : PubMed/NCBI
4	Redondo M, Villar E, Torres-Munoz J, Tellez T, Morell M and Petito CK: Overexpression of clusterin in human breast carcinoma. Am J Pathol. 157:393–399. 2000. View Article : Google Scholar : PubMed/NCBI
5	Miyake H, Gleave M, Kamidono S and Hara I: Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. Urology. 59:150–154. 2002. View Article : Google Scholar : PubMed/NCBI
6	Xie D, Lau SH, Sham JS, et al: Up-regulated expression of cytoplasmic clusterin in human ovarian carcinoma. Cancer. 103:277–283. 2005. View Article : Google Scholar : PubMed/NCBI
7	Kang YK, Hong SW, Lee H and Kim WH: Overexpression of clusterin in human hepatocellular carcinoma. Hum Pathol. 35:1340–1346. 2004. View Article : Google Scholar : PubMed/NCBI
8	Miyake H, Hara S, Arakawa S, Kamidono S and Hara I: Overexpression of clusterin is an independent prognostic factor for nonpapillary renal cell carcinoma. J Urol. 167:703–706. 2002. View Article : Google Scholar : PubMed/NCBI
9	Leskov KS, Klokov DY, Li J, Kinsella TJ and Boothman DA: Synthesis and functional analyses of nuclear clusterin, a cell death protein. J Biol Chem. 278:11590–11600. 2003. View Article : Google Scholar : PubMed/NCBI
10	Moretti RM, Marelli MM, Mai S, et al: Clusterin isoforms differentially affect growth and motility of prostate cells: possible implications in prostate tumorigenesis. Cancer Res. 67:10325–10333. 2007. View Article : Google Scholar
11	Tenniswood M, Flanagan L, Whyte L and Chatterjee N: Effects of clusterin over-expression on metastatic progression and therapy in breast cancer. BMC Cancer. 10:1072010. View Article : Google Scholar : PubMed/NCBI
12	Wu AJ, Park II, Zhaung L and Lee C: Response to a lethal dose of heat shock by a transient up-regulation of clusterin expression followed by down-regulation and apoptosis in prostate and bladder cancer cells. Prostate. 53:277–285. 2002. View Article : Google Scholar : PubMed/NCBI
13	Sensibar JA, Sutkowski DM, Raffo A, et al: Prevention of cell death induced by tumor necrosis factor alpha in LNCaP cells by overexpression of sulfated glycoprotein-2 (clusterin). Cancer Res. 55:2431–2437. 1995.PubMed/NCBI
14	Miyake H, Nelson C, Rennie PS and Gleave ME: Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res. 60:170–176. 2000.PubMed/NCBI
15	Scaltriti M, Santamaria A, Paciucci R and Bettuzzi S: Intracellular clusterin induces G2-M phase arrest and cell death in PC-3 prostate cancer cells1. Cancer Res. 64:6174–6182. 2004. View Article : Google Scholar : PubMed/NCBI
16	Faivre S, Kroemer G and Raymond E: Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 5:671–688. 2006. View Article : Google Scholar : PubMed/NCBI
17	Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
18	Downward J: Targeting RAS and PI3K in lung cancer. Nat Med. 14:1315–1316. 2008. View Article : Google Scholar : PubMed/NCBI
19	Gustafson AM, Soldi R, Anderlind C, et al: Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Transl Med. 2:26ra252010. View Article : Google Scholar : PubMed/NCBI
20	Luo J, Manning BD and Cantley LC: Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 4:257–262. 2003. View Article : Google Scholar : PubMed/NCBI
21	Wang J, Zhang N, Li B, et al: Decline of serum CYFRA21-1 during chemoradiotherapy of NSCLC: a probable predictive factor for tumor response. Tumour Biol. 32:689–695. 2011. View Article : Google Scholar : PubMed/NCBI
22	Resnicoff M, Ambrose D, Coppola D and Rubin R: Insulin-like growth factor-1 and its receptor mediate the autocrine proliferation of human ovarian carcinoma cell lines. Lab Invest. 69:756–760. 1993.PubMed/NCBI
23	Schneider MR, Lahm H, Wu M, Hoeflich A and Wolf E: Transgenic mouse models for studying the functions of insulin-like growth factor-binding proteins. FASEB J. 14:629–640. 2000.PubMed/NCBI
24	LeRoith D, Werner H, Beitner-Johnson D and Roberts CT Jr: Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 16:143–163. 1995. View Article : Google Scholar
25	Saltiel AR and Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 414:799–806. 2001. View Article : Google Scholar : PubMed/NCBI
26	Myers MG Jr, Sun XJ, Cheatham B, et al: IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3′-kinase. Endocrinology. 132:1421–1430. 1993.
27	Adams TE, Epa VC, Garrett TP and Ward CW: Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci. 57:1050–1093. 2000. View Article : Google Scholar : PubMed/NCBI
28	Baserga R, Peruzzi F and Reiss K: The IGF-1 receptor in cancer biology. International journal of cancer. Int J Cancer. 107:873–877. 2003. View Article : Google Scholar : PubMed/NCBI
29	Gualberto A and Pollak M: Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene. 28:3009–3021. 2009. View Article : Google Scholar : PubMed/NCBI
30	Ulanet DB, Ludwig DL, Kahn CR and Hanahan D: Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. Proc Natl Acad Sci USA. 107:10791–10798. 2010. View Article : Google Scholar
31	Ko JC, Hong JH, Wang LH, et al: Role of repair protein Rad51 in regulating the response to gefitinib in human non-small cell lung cancer cells. Mol Cancer Ther. 7:3632–3641. 2008. View Article : Google Scholar : PubMed/NCBI
32	Gridelli C, Rossi A and Maione P: Treatment of non-small-cell lung cancer: state of the art and development of new biologic agents. Oncogene. 22:6629–6638. 2003. View Article : Google Scholar : PubMed/NCBI
33	Pallis AG, Serfass L, Dziadziusko R, et al: Targeted therapies in the treatment of advanced/metastatic NSCLC. Eur J Cancer. 45:2473–2487. 2009. View Article : Google Scholar : PubMed/NCBI
34	Carney DN: Lung cancer--time to move on from chemotherapy. N Engl J Med. 346:126–128. 2002. View Article : Google Scholar : PubMed/NCBI
35	Baserga R: The IGF-I receptor in cancer research. Exp Cell Res. 253:1–6. 1999. View Article : Google Scholar : PubMed/NCBI
36	Petropoulou C, Trougakos IP, Kolettas E, Toussaint O and Gonos ES: Clusterin/apolipoprotein J is a novel biomarker of cellular senescence that does not affect the proliferative capacity of human diploid fibroblasts. FEBS Lett. 509:287–297. 2001. View Article : Google Scholar
37	Stahel RA and Zangemeister-Wittke U: Antisense oligonucleotides for cancer therapy-an overview. Lung Cancer. 41(Suppl 1): S81–S888. 2003. View Article : Google Scholar : PubMed/NCBI
38	Suzuki CM, Goetz E, Veneziano G, et al: Secretory clusterin (sCLU) is a hallmark sensor of DNA damage, cell stress, and cellular senescence: Evidence for similar regulation of sCLU expression after cellular stress and replicative senescence. ICS. 1299:150–157. 2007.
39	Zellweger T, Miyake H, July LV, Akbari M, Kiyama S and Gleave ME: Chemosensitization of human renal cell cancer using antisense oligonucleotides targeting the antiapoptotic gene clusterin. Neoplasia. 3:360–367. 2001. View Article : Google Scholar : PubMed/NCBI
40	Jo H, Jia Y, Subramanian KK, Hattori H and Luo HR: Cancer cell-derived clusterin modulates the phosphatidylinositol 3′-kinase-Akt pathway through attenuation of insulin-like growth factor 1 during serum deprivation. Mol Cell Biol. 28:4285–4299. 2008.PubMed/NCBI
41	Goetz EM, Shankar B, Zou Y, et al: ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability. Oncogene. 30:3745–3754. 2011. View Article : Google Scholar : PubMed/NCBI
42	Ammar H and Closset JL: Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 283:12851–12861. 2008. View Article : Google Scholar : PubMed/NCBI
43	Rychahou PG, Jackson LN, Silva SR, Rajaraman S and Evers BM: Targeted molecular therapy of the PI3K pathway: therapeutic significance of PI3K subunit targeting in colorectal carcinoma. Ann Surg. 243:833–842; discussion 843–834. 2006. View Article : Google Scholar : PubMed/NCBI
44	Pitt SC, Chen H and Kunnimalaiyaan M: Inhibition of phosphatidylinositol 3-kinase/Akt signaling suppresses tumor cell proliferation and neuroendocrine marker expression in GI carcinoid tumors. Ann Surg Oncol. 16:2936–2942. 2009. View Article : Google Scholar : PubMed/NCBI
45	Li C, Liu VW, Chan DW, Yao KM and Ngan HY: LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells. Int J Gynecol Cancer. 22:15–22. 2012. View Article : Google Scholar : PubMed/NCBI