Oncogenic activity of insulin in the development of non‑small cell lung carcinoma

Jiang,Jie; Ren,Hong‑Yue; Geng,Guo‑Jun; Mi,Yan‑Jun; Liu,Yu; Li,Ning; Yang,Shu‑Yu; Shen,Dong‑Yan

doi:10.3892/ol.2017.7347

Oncogenic activity of insulin in the development of non‑small cell lung carcinoma

Authors:
- Jie Jiang
- Hong‑Yue Ren
- Guo‑Jun Geng
- Yan‑Jun Mi
- Yu Liu
- Ning Li
- Shu‑Yu Yang
- Dong‑Yan Shen
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Affiliations: Department of Thoracic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China, Department of Pathology, The Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, P.R. China, Department of Biobank, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China, Department of Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China
Published online on: November 3, 2017 https://doi.org/10.3892/ol.2017.7347
Pages: 447-452

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Abstract

Insulin is associated with the progression of numerous different types of cancer. However, the association between insulin and non‑small cell lung carcinoma (NSCLC) remains unknown. The aim of the present study was to evaluate the role of insulin in the proliferation, migration and drug resistance of NSCLC cells, and to determine whether the phosphoinositide 3‑kinase/protein kinase B (PI3K/Akt) pathway was involved. NSCLC cells were treated with insulin in the absence or presence of LY294002, an inhibitor of the PI3K/Akt pathway. Following co‑incubation with insulin, cell proliferation and drug resistance were measured by MTT; cell migration was examined by wound healing and Transwell assays; and the expression of cyclin A, proliferating cell nuclear antigen (PCNA), p27, matrix metalloproteinase 3 (MMP3), P‑gp and proteins involved in the PI3K/Akt pathway were assessed via western blotting. The results of the current study demonstrated that insulin enhanced the proliferation, migration and drug resistance of NSCLC cells. Correspondingly, insulin upregulated the expression of cyclin A, PCNA, MMP3, P‑gp and downregulated p27 expression in NSCLC cells. Following treatment with insulin, it was demonstrated that phospho‑Akt expression increased in a dose‑dependent manner. However, the effects of insulin on NSCLC cells was inhibited by the PI3K/Akt pathway inhibitor LY294002. Therefore, the results of the current study indicate that insulin is associated with the development of NSCLC by activating the PI3K/Akt pathway. This may improve understanding of the mechanism of action of insulin in NSCLC in the future.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Eng J Med. 359:1367–1380. 2008. View Article : Google Scholar
3	Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezinek I, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 11:521–529. 2010. View Article : Google Scholar : PubMed/NCBI
4	Spiro SG and Silvestri GA: One hundred years of lung cancer. Am J Res Crit Care Med. 172:523–529. 2005. View Article : Google Scholar
5	van Zandwijk N and Fong KM: Update in lung cancer: Prologue to a modern review series. Respirology. 20:183–184. 2015. View Article : Google Scholar : PubMed/NCBI
6	Wolin KY, Carson K and Colditz GA: Obesity and cancer. Oncologist. 15:556–565. 2010. View Article : Google Scholar : PubMed/NCBI
7	Renehan AG, Tyson M, Egger M, Heller RF and Zwahlen M: Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet. 371:569–578. 2008. View Article : Google Scholar : PubMed/NCBI
8	Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, Botezelli JD, Asadi A, Hoffman BG, Kieffer TJ, et al: Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16:723–737. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tseng CH: Use of insulin and mortality from breast cancer among taiwanese women with diabetes. J Diabetes Res. 2015:6787562015. View Article : Google Scholar : PubMed/NCBI
10	Tseng CH: Diabetes, insulin use, smoking, and pancreatic cancer mortality in Taiwan. Acta Diabetol. 50:879–886. 2013. View Article : Google Scholar : PubMed/NCBI
11	Wang L, Cai S, Teng Z, Zhao X, Chen X and Bai X: Insulin therapy contributes to the increased risk of colorectal cancer in diabetes patients: A meta-analysis. Diagn Pathol. 8:1802013. View Article : Google Scholar : PubMed/NCBI
12	Tseng CH: Insulin use and smoking jointly increase the risk of bladder cancer mortality in patients with type 2 diabetes. Clin Genitourin Cancer. 11:508–514. 2013. View Article : Google Scholar : PubMed/NCBI
13	Chan MT, Lim GE, Skovsø S, Yang YH, Albrecht T, Alejandro EU, Hoesli CA, Piret JM, Warnock GL and Johnson JD: Effects of insulin on human pancreatic cancer progression modeled in vitro. BMC Cancer. 14:8142014. View Article : Google Scholar : PubMed/NCBI
14	Tomas NM, Masur K, Piecha JC, Niggemann B and Zänker KS: Akt and phospholipase Cgamma are involved in the regulation of growth and migration of MDA-MB-468 breast cancer and SW480 colon cancer cells when cultured with diabetogenic levels of glucose and insulin. BMC Res Notes. 5:2142012. View Article : Google Scholar : PubMed/NCBI
15	Wei Z, Liang L, Junsong L, Rui C, Shuai C, Guanglin Q, Shicai H, Zexing W, Jin W, Xiangming C and Shufeng W: The impact of insulin on chemotherapeutic sensitivity to 5-fluorouracil in gastric cancer cell lines SGC7901, MKN45 and MKN28. J Exp Clin Cancer Res. 34:642015. View Article : Google Scholar : PubMed/NCBI
16	Zhang C, Lan T, Hou J, Li J, Fang R, Yang Z, Zhang M, Liu J and Liu B: NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling. Oncotarget. 5:4392–4405. 2014. View Article : Google Scholar : PubMed/NCBI
17	Sarker D, Reid AH, Yap TA and de Bono JS: Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res. 15:4799–4805. 2009. View Article : Google Scholar : PubMed/NCBI
18	Safdari Y, Khalili M, Ebrahimzadeh MA, Yazdani Y and Farajnia S: Natural inhibitors of PI3K/AKT signaling in breast cancer: Emphasis on newly-discovered molecular mechanisms of action. Pharmacol Res. 93:1–10. 2015. View Article : Google Scholar : PubMed/NCBI
19	Martini M, De Santis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signaling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014. View Article : Google Scholar : PubMed/NCBI
20	Huang GL, Luo Q, Rui G, Zhang W, Zhang QY, Chen QX and Shen DY: Oncogenic activity of retinoic acid receptor γ is exhibited through activation of the Akt/NF-κB and Wnt/β-catenin pathways in cholangiocarcinoma. Mol Cell Biol. 33:3416–3425. 2013. View Article : Google Scholar : PubMed/NCBI
21	Liu S, Li Y, Lin T, Fan X, Liang Y and Heemann U: High dose human insulin and insulin glargine promote T24 bladder cancer cell proliferation via PI3K-independent activation of Akt. Diabetes Res Clin Pract. 91:177–182. 2011. View Article : Google Scholar : PubMed/NCBI
22	Kessler II: Cancer and diabetes mellitus. A review of the literature. J Chronic Dis. 23:579–600. 1971. View Article : Google Scholar : PubMed/NCBI
23	Home P: Insulin therapy and cancer. Diabetes Care. 36 Suppl 2:S240–S244. 2013. View Article : Google Scholar : PubMed/NCBI
24	Mattarocci S, Abbruzzese C, Mileo AM, Visca P, Antoniani B, Alessandrini G, Facciolo F, Felsani A, Radulescu RT and Paggi MG: Intracellular presence of insulin and its phosphorylated receptor in non-small cell lung cancer. J Cell Physiol. 221:766–770. 2009. View Article : Google Scholar : PubMed/NCBI
25	Kling J: Inhaled insulin's last gasp? Nat Biotechnol. 26:479–480. 2008. View Article : Google Scholar : PubMed/NCBI
26	White PB, True EM, Ziegler KM, Wang SS, Swartz-Basile DA, Pitt HA and Zyromski NJ: Insulin, leptin, and tumoral adipocytes promote murine pancreatic cancer growth. J Gastrointest Surg. 14:1888–1894. 2010. View Article : Google Scholar : PubMed/NCBI
27	Chappell J, Leitner JW, Solomon S, Golovchenko I, Goalstone ML and Draznin B: Effect of insulin on cell cycle progression in MCF-7 breast cancer cells. Direct and potentiating influence. J Biol Chem. 276:38023–38028. 2001.PubMed/NCBI
28	Iqbal MA, Siddiqui FA, Gupta V, Chattopadhyay S, Gopinath P, Kumar B, Manvati S, Chaman N and Bamezai RN: Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Mol Cancer. 12:722013. View Article : Google Scholar : PubMed/NCBI
29	Kim JS, Kim ES, Liu D, Lee JJ, Solis L, Behrens C, Lippman SM, Hong WK, Wistuba II and Lee HY: Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer. Cancer. 118:2454–2465. 2012. View Article : Google Scholar : PubMed/NCBI
30	Han CH, Cho JY, Moon JT, Kim HJ, Kim SK, Shin DH, Chang J, Ahn CM, Kim SK and Chang YS: Clinical significance of insulin receptor substrate-I down-regulation in non-small cell lung cancer. Oncol Rep. 16:1205–1210. 2006.PubMed/NCBI