Role of autophagy in high linear energy transfer radiation-induced cytotoxicity to tumor cells.
Bottom Line: Heavy-ion radiotherapy has a potential advantage over conventional radiotherapy due to improved dose distribution and a higher biological effectiveness in cancer therapy.The ability of carbon ions to inhibit the activation of the PI3K/Akt pathway rose with increasing their LET.Our data imply that targeting autophagy might enhance the effectiveness of heavy-ion radiotherapy.
Affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, China.Show MeSH
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Mentions: To elucidate the molecular mechanisms of radiosensitization by inhibiting autophagy, HeLa and MDA-MB-231 cells pretreated with autophagy inhibitor or promoter were irradiated with the carbon ions of 75 keV/μm at 2 Gy and then the cell apoptosis was measured at 4 or 24 h after irradiation. The apoptotic rates of HeLa cells induced by the carbon ions were significantly higher in the presence of 3-MA than those induced by irradiation alone at 4 and 24 h post-irradiation. On the contrary, cell apoptosis was suppressed in the presence of rapamycin at 4 h significantly and 24 h post-irradiation (Figs 6a,S3). Moreover, the protein expression of cleaved caspase-3 increased in HeLa cells cotreated with 3-MA but decreased in the case of cotreatment with rapamycin, as shown in Figure 6(b). Figure 6(c) details the flow cytometric measurements of DNA fragmentation in MDA-MB-231 cells at 24 h after irradiation. The profiles indicate that the high-LET radiation increased the apoptotic rate of MDA-MB-231 cells at 24 h post-irradiation, whereas this effect was reduced or promoted by cotreatment with rapamycin or CQ. Western blot analysis of cleaved caspase-3 in MDA-MB-231 cells is shown in Figure 6(d). Once again, the results obtained in the apoptosis measurements above were confirmed at the level of protein expression. Clearly, these results indicated that inhibition or promotion of autophagy enhanced or mitigated the high-LET radiation-induced apoptosis in HeLa and MDA-MB-231 cell lines.
Affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, China.