Yi Li1, Kui Lu2, Ben Zhao3, Xiaokui Zeng4, Shan Xu5, Xin Ma4,6, Yunqing Zhi1,4,7. 1. Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China. 2. Department of Oncology, the Second People's Hospital of Taizhou City, Taizhou, China. 3. Division of Solid Tumor Translational Oncology, German Cancer Consortium and German Cancer Research Center, DKFZ, Heidelberg, Germany. 4. Department of Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 5. Department of Radiotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 6. Department of Nephrology, the First Affiliated Hospital of Chengdu Medical College, Chengdu, China. 7. Department of Gynecology, Shanghai Changning Maternity and Infant Health Hospital, Shanghai, China.
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. 2020 Journal of Gastrointestinal Oncology. All rights reserved.
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. 2020 Journal of Gastrointestinal Oncology. All rights reserved.
Authors: Luis Alberto Henríquez-Hernández; Marta Lloret; Beatriz Pinar; Elisa Bordón; Agustín Rey; Amina Lubrano; Pedro Carlos Lara Journal: Gynecol Oncol Date: 2011-06-25 Impact factor: 5.482
Authors: Oliver Riesterer; Qiuan Yang; Uma Raju; Mylin Torres; David Molkentine; Nalini Patel; David Valdecanas; Luka Milas; K Kian Ang Journal: Int J Radiat Oncol Biol Phys Date: 2010-12-02 Impact factor: 7.038
Authors: Myung Woul Han; In Sun Ryu; Jong Cheol Lee; Song Hee Kim; Hyo Won Chang; Yoon Sun Lee; Seulkina Lee; Seong Who Kim; Sang Yoon Kim Journal: Oral Oncol Date: 2018-02-20 Impact factor: 5.337
Authors: Matias E Valsecchi; Mary McDonald; Jonathan R Brody; Terry Hyslop; Boris Freydin; Charles J Yeo; Charalambos Solomides; Stephen C Peiper; Agnieszka K Witkiewicz Journal: Cancer Date: 2011-11-15 Impact factor: 6.860