| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 103 === Radiotherapy (RT) is one of the major modalities of cancer treatment of patients with solid tumor, often in combination with surgery, chemotherapy or target therapy. Increasing radiosensitivity is the major strategy to improve the efficacy of RT. RT provides anti-tumor effect through its direct pro-apoptotic effect, but it also can induce radio-protective signal pathway including PI3K/Akt/mTOR pathway, one reason of radioresistance.
We demonstrated radiation-induced activation of PI3K/Akt/mTOR pathway and VEGF-C protein with dose- and time-dependent increase in A549 cancer cells. Radiation induced VEGF-C expression was down-regulated by LY294002 and rapamycin through attenuating the AKT/mTOR signaling pathway.
Radiation-induced Akt/mTOR phosphorylation and VEGF-C up-regulation in A549 cells were inhibited by Akt siRNA. It is indicating that PI3K/Akt/mTOR signaling mediates irradiation-induced VEGF-C expression. Furthermore, the irradiated supernatant promoted HUVEC and LEC proliferation, which was inhibited by VEGF-C-siRNA expression in A 549 cancer cells. The data demonstrated the mechanism of radioresistance through radiation-induced activation of PI3K/Akt/mTOR pathway, subsequently increasing VEGF-C expression in cancer cells and promoting endothelial cell proliferation.
Furthermore, the combination of dual PI3K/Akt/mTOR pathway inhibitor, BEZ235, pretreatment and radiation resulted in an increased cell apoptosis, and a significantly increased number of γ-H2AX/cell (DNA double strand breaks). BEZ235 not only inhibited PI3K/Akt/mTOR pathway but also inhibited ATM and DNA-PKcs activity to enhance radiosensitivity. In vivo model, the tumor size and the expression pattern of p-mTOR, p-eIF4E, and p-rpS6 were significantly decreased in combined group than radiation alone or BEZ235 alone. Our findings indicate that the administration of BEZ235 before radiation enhances the radiotherapeutic effect of colorectal cancer cells both in vitro and in vivo.
These encouraging data demonstrated the mechanism of radioresistance through radiation-induced activation of PI3K/Akt/mTOR pathway, subsequently increasing VEGF-C expression and promoting endothelial cell proliferation. The dual PI3K/Akt/mTOR inhibitor could enhance the radiotherapeutic effect. The further clinical study need to approve PI3K/Akt/mTOR inhibitor combination with RT in colorectal cancer treatment.
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