Insulin-like Growth Factor 1 Receptor Promotes the Growth and Chemoresistance of Pancreatic Cancer

Overview

Journal Dig Dis Sci

Specialty Gastroenterology

Date 2013 Apr 17

PMID 23589145

Citations 16

Authors

Xiaodong Tian

Kun Hao

Changfu Qin

Kun Xie

Xuehai Xie

Yinmo Yang

Affiliations

Soon will be listed here.

Abstract

Background: Insulin-like growth factor 1 receptor (IGF1R) plays important roles in the progression of pancreatic cancer. However, the underlying mechanism remains unclear.

Aims: The purpose of this study was to investigate the effects of IGF1R knockdown on the proliferation, apoptosis and chemosensitivity of pancreatic cancer cells, and explore the possible mechanisms.

Methods: Pancreatic cancer cells expressing IGF1R shRNA were established, and the cell proliferation, colony formation, and chemosensitivity to gemcitabine were examined in vitro. The activation of AKT and NF-κB was detected by Western blot analysis and luciferase assay, respectively. Xenograft mice models were established to evaluate the in vivo anti-tumor effects of IGF1R knockdown.

Results: IGF1R knockdown notably inhibited pancreatic cancer cell proliferation and colony formation, induced apoptosis, and inhibited xenograft tumor growth. Moreover, IGF1R knockdown significantly enhanced chemosensitivity to gemcitabine in pancreatic cancer cells, and this was correlated with the inhibition of PI3K/AKT and NF-κB pathways.

Conclusions: IGF1R knockdown suppresses tumor growth and enhances chemosensitivity in pancreatic cancer via the inhibition of PI3K/AKT and NF-κB pathways, and is a promising approach to overcome the chemoresistance of pancreatic cancer.

Citing Articles

Obesity and endocrine-related cancer: The important role of IGF-1.

Zhong W, Wang X, Wang Y, Sun G, Zhang J, Li Z Front Endocrinol (Lausanne). 2023; 14:1093257.

PMID: 36755926 PMC: 9899991. DOI: 10.3389/fendo.2023.1093257.

Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy.

Giatagana E, Berdiaki A, Gaardlos M, Samsonov S, N Tzanakakis G, Nikitovic D Cancers (Basel). 2022; 14(5).

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An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma.

Xiao Z, Li J, Yu Q, Zhou T, Duan J, Yang Z Front Pharmacol. 2022; 12:778294.

PMID: 35002712 PMC: 8733666. DOI: 10.3389/fphar.2021.778294.

Downregulation of the let-7 family of microRNAs may promote insulin receptor/insulin-like growth factor signalling pathways in pancreatic ductal adenocarcinoma.

Nweke E, Brand M Oncol Lett. 2020; 20(3):2613-2620.

PMID: 32782579 PMC: 7400736. DOI: 10.3892/ol.2020.11854.

Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer.

Thomas D, Radhakrishnan P Cancers (Basel). 2020; 12(5).

PMID: 32414222 PMC: 7281733. DOI: 10.3390/cancers12051228.

References

Ii M, Li H, Adachi Y, Yamamoto H, Ohashi H, Taniguchi H . The efficacy of IGF-I receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras mutation status. Clin Cancer Res. 2011; 17(15):5048-59. DOI: 10.1158/1078-0432.CCR-10-3131. View

Ng S, Tsao M, Nicklee T, Hedley D . Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res. 2001; 7(10):3269-75. View

Miljkovic M, Girotra M, Abraham R, Erlich R . Novel medical therapies of recurrent and metastatic gastroenteropancreatic neuroendocrine tumors. Dig Dis Sci. 2011; 57(1):9-18. DOI: 10.1007/s10620-011-1854-0. View

Sclabas G, Fujioka S, Schmidt C, Evans D, Chiao P . NF-kappaB in pancreatic cancer. Int J Gastrointest Cancer. 2003; 33(1):15-26. DOI: 10.1385/IJGC:33:1:15. View

Sachdev D, Yee D . Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007; 6(1):1-12. DOI: 10.1158/1535-7163.MCT-06-0080. View

Arlt A, Schafer H . NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther. 2002; 40(8):336-47. DOI: 10.5414/cpp40336. View

Reddy S, Huang J, Liao W . Phosphatidylinositol 3-kinase as a mediator of TNF-induced NF-kappa B activation. J Immunol. 2000; 164(3):1355-63. DOI: 10.4049/jimmunol.164.3.1355. View

Chen D, Niu M, Jiao X, Zhang K, Liang J, Zhang D . Inhibition of AKT2 enhances sensitivity to gemcitabine via regulating PUMA and NF-κB signaling pathway in human pancreatic ductal adenocarcinoma. Int J Mol Sci. 2012; 13(1):1186-1208. PMC: 3269746. DOI: 10.3390/ijms13011186. View

Beltran P, Mitchell P, Chung Y, Cajulis E, Lu J, Belmontes B . AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells. Mol Cancer Ther. 2009; 8(5):1095-105. DOI: 10.1158/1535-7163.MCT-08-1171. View

10.

Liang Q, Wang B, Chen G, Li G, Xu Y . Clinical significance of vascular endothelial growth factor and connexin43 for predicting pancreatic cancer clinicopathologic parameters. Med Oncol. 2009; 27(4):1164-70. DOI: 10.1007/s12032-009-9354-1. View

11.

Miller B, Yee D . Type I insulin-like growth factor receptor as a therapeutic target in cancer. Cancer Res. 2005; 65(22):10123-7. DOI: 10.1158/0008-5472.CAN-05-2752. View

12.

Schniewind B, Christgen M, Kurdow R, Haye S, Kremer B, Kalthoff H . Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Int J Cancer. 2004; 109(2):182-8. DOI: 10.1002/ijc.11679. View

13.

Yan H, Liu W, Sun W, Wu J, Ji M, Wang Q . miR-17-5p inhibitor enhances chemosensitivity to gemcitabine via upregulating Bim expression in pancreatic cancer cells. Dig Dis Sci. 2012; 57(12):3160-7. DOI: 10.1007/s10620-012-2400-4. View

14.

Bergmann U, Funatomi H, Yokoyama M, Beger H, Korc M . Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res. 1995; 55(10):2007-11. View

15.

Olmos D, Tan D, Jones R, Judson I . Biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor monoclonal antibodies in treating sarcoma: twenty years from the bench to the bedside. Cancer J. 2010; 16(3):183-94. DOI: 10.1097/PPO.0b013e3181dbebf9. View

16.

Shu S, Yang Y, Li X, Li T, Zhang Y, Xu C . Down-regulation of IGF-1R expression inhibits growth and enhances chemosensitivity of endometrial carcinoma in vitro. Mol Cell Biochem. 2011; 353(1-2):225-33. DOI: 10.1007/s11010-011-0790-9. View

17.

Zhang H, Sachdev D, Wang C, Hubel A, Gaillard-Kelly M, Yee D . Detection and downregulation of type I IGF receptor expression by antibody-conjugated quantum dots in breast cancer cells. Breast Cancer Res Treat. 2008; 114(2):277-85. DOI: 10.1007/s10549-008-0014-5. View

18.

Burris 3rd H, Moore M, Andersen J, Green M, Rothenberg M, Modiano M . Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997; 15(6):2403-13. DOI: 10.1200/JCO.1997.15.6.2403. View