Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer

Abstract

Background: Although radiation therapy for advanced colorectal cancer (CRC) is very effective in some patients, treatment resistance limits its efficacy. Insulin-like growth factor 1 receptor (IGF1R) can affect tumor responsiveness and sensitivity to radiation in several cancer types. Herein, we studied the underlying function of IGF1R in the resistance of advanced CRC to radiation therapy and the possible use of drugs targeting IGF1R to overcome this resistance in patients with CRC.Methods: Differences in the expression levels of the IGF1R were assessed in CRC samples from patients who were radiosensitive or radioresistant. Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for in vitro studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807. We assessed radiosensitivity in these human CRC cells lines by examining their proliferation and colony formation, as well as cell cycle analysis. Activation of the Akt pathway was assessed using western blotting.Results: Compared with tissues from radiosensitive patients, higher IGF1R expression levels were found in patients with radiation-resistant colorectal cancer, while BMS-754807 had improved radiosensitivity and reversed radiation tolerance in both colorectal cancer cell lines. Pre-treatment with BMS-754807 prior to irradiation inhibited Akt phosphorylation, induced cell cycle arrest, and increased DNA damage. Therefore, the IGF1R contributes to radiation resistance of CRC cells in vitro.Conclusions: This study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.

Multiomic analysis of the anoikis genes in colon cancer based on bioinformatics

“…In the study by Aaron J Scott et al [29], it was observed that Dasatinib-sensitive CRC cell lines exhibited G1 inhibition, and the antitumor effect resulted from G1 cell cycle arrest, which proved that Dasatinib did have a certain effect on colon cancer. Yi Li et al mentioned in their study on IGF1R [30] that BMS-754807 had improved radiosensitivity and reversed radiation resistance in two colorectal cancer cell lines. Regarding AZD8055, currently only related literatures can be found in renal cell carcinoma, cholangiocarcinoma and breast cancer [31].…”

The Insulin-like Growth Factor System and Colorectal Cancer

“…IGF1R depletion/inhibition sensitizes CRC cells to radiotherapy (converting them to radiosensitive), as shown in HT-29 and SW480 cell lines where IGF1R was inhibited by NVP-ADW742 [ 213 ] and in HT-29, SW480 and DLD-1 cells pretreated with BMS-754807 [ 214 ]. The inhibitory effect of BMS-754807 on colon cancer cell growth was stronger compared to the effect of linsitinib, and the anti-neoplastic effect was mostly independent of IGF1R [ 215 ].…”

Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response

“…Since DNA treatment via TLR9 can exert its effects in both MyD88-dependent and MyD88-independent ways, it is also important that the MyD88-dependent and MyD88-independent TLR signaling pathways are intact in HT29 cells [ 26 ]. IGF1R expression in HT29 cells is moderate as compared to other CRC cell lines (e.g., SW480 or DLD-1) [ 27 ]. Also, in HT29 cells, elevated IGF2 expression can be detected, which is essential for both autocrine activation of IGF1R signaling and studying the effect of IGF1R inhibition [ 28 ].…”