Abstract
Reduced sensitivity of prostate cancer (PC) cells to radiation therapy poses a significant challenge in the clinic. Activation of epidermal growth factor receptor (EGFR), type 1 insulin-like growth factor receptor (IGF1R), and crosstalk between these two signaling pathways have been implicated in the development of radiation resistance in PC. This study assessed the effects of targeting both receptors on the regulation of radio-sensitivity in PC cells. Specific inhibitors of EGFR and IGF1R, Erlotinib and AG1024, as well as siRNA targeting EGFR and IGF1R, were used to radio-sensitize PC cells. Our results showed that co-inhibiting both receptors significantly dampened cellular growth and DNA damage repair, and increased radio-sensitivity in PC cells. These effects were carried out through synergistic inhibition of homologous recombination-directed DNA repair (HRR), but not via inhibition of non-homologous end joining (NHEJ). Furthermore, the compromised HRR capacity was caused by reduced phosphorylation of insulin receptor substrate 1 (IRS1) and its subsequent interaction with Rad51. The synergistic effect of the EGFR and IGF1R inhibitors was also confirmed in nude mouse xenograft assay. This is the first study testing co-inhibiting EGFR and IGF1R signaling in the context of radio-sensitivity in PC and it may provide a promising adjuvant therapeutic approach to improve the outcome of PC patients to radiation treatment.
Highlights
Prostate cancer (PC) is the most common malignancy and the second leading cause of cancer-related deaths among male patients [1]
Our data showed that tumor cell viability was significantly reduced and tumor cell apoptosis enhanced by irradiation following inhibition of both epidermal growth factor receptor (EGFR) and IGF1R, as compared to irradiation treatment alone or irradiation plus blocking of either receptor (Figure 1A, B)
We investigated whether co-targeting of EGFR and IGF1R could sensitize PC cells to c-irradiation
Summary
Prostate cancer (PC) is the most common malignancy and the second leading cause of cancer-related deaths among male patients [1]. Many patients eventually developed a hormone-refractory disease due to the growth of androgen-refractory cancer cells, which leads to failure of androgen ablation therapy and leaves patients with fewer therapeutic options [3,4]. Combination of definitive local therapies, such as radical prostatectomy together with adjuvant radiotherapy, has been demonstrated to improve the survival of PC patients [5,6]. Such therapy is challenged by the emergence of resistance in tumor cells. It is, of paramount importance to develop novel therapeutic strategies to overcome radioresistance and improve radio-sensitivity by targeting molecular machineries in androgen-independent PC cells
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