The impact of the IGF-1 system of cancer cells on radiation response - An in vitro study

Senthiladipan Venkatachalam; Esther Mettler; Christian Fottner; Matthias Miederer; Bernd Kaina; Matthias M Weber

doi:10.1016/j.ctro.2017.09.006

The impact of the IGF-1 system of cancer cells on radiation response - An in vitro study

Clin Transl Radiat Oncol. 2017 Oct 5:7:1-8. doi: 10.1016/j.ctro.2017.09.006. eCollection 2017 Dec.

Authors

Senthiladipan Venkatachalam¹, Esther Mettler¹, Christian Fottner¹, Matthias Miederer², Bernd Kaina³, Matthias M Weber¹

Affiliations

¹ Department of Endocrinology and Metabolic Diseases, University Medical Center, Mainz, Germany.
² Department of Nuclear Medicine, University Medical Center, Mainz, Germany.
³ Institute of Toxicology, University Medical Center, Mainz, Germany.

Abstract

Background: Overexpression of the insulin-like growth factor-1 receptor (IGF-1R) is associated with increased cell proliferation, differentiation, transformation, and tumorigenicity. Additionally, signaling involved in the resistance of cancer cells to radiotherapy originates from IGF-1R. The purpose of this study was to investigate the role of the IGF-1 system in the radiation response and further evaluate its effect on the expression of DNA repair pathway genes.

Methods: To inhibit the IGF-1 system, we stably transfected the Caco-2 cell line to express a kinase-deficient IGF-1R mutant. We then studied the effects of this mutation on cell growth, the response to radiation, and clonogenic survival, as well as using a cell viability assay to examine DNA damage and repair. Finally, we performed immunofluorescence for γ-H2AX to examine double-strand DNA breaks and evaluated the expression of 84 key genes involved in DNA repair with a real-time PCR array.

Results: Mutant IGF-1R cells exhibited significantly blunted cell growth and viability, compared to wild-type cells, as well as reduced clonogenic survival after γ-irradiation. However, mutant IGF-1R cells did not show any significant delays in the repair of radiation-induced DNA double-strand breaks. Furthermore, expression of mutant IGF-1R significantly down-regulated the mRNA levels of BRCA2, a major protein involved in homologous recombination DNA repair.

Conclusion: These results indicate that blocking the IGF-1R-mediated signaling cascade, through the expression of a kinase-deficient IGF-1R mutant, reduces cell growth and sensitizes cancer cells to ionizing radiation. Therefore, the IGF-1R system could be a potential target to enhance radio-sensitivity and the efficacy of cancer treatments.

Keywords: BAX, BCL-2-associated X; BCL-2, B-cell lymphoma 2; BRCA2; Caco-2-KR4, IGF-1R/KR clone number 4; Colorectal carcinmoma; Dominant negative mutant; HRR, homologous recombination repair; IGF-1R, insulin-like growth factor 1 receptor; IGF-1R/KR, kinase-deficient IGF-1R; IRS-1, insulin receptor substrate 1; Insulin-like growth factor-1 receptor; MVP, major vault protein; NHEJ, non-homologous end joining; PTEN, phosphatase and tensin homolog; RAD 51; Radiosensitivity; SF, surviving fractions.