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 explore the molecular mechanism underlying the autophagy induction by the carbon ions with different LETs (LET = 13 and 75 keV/μm) in tumor cells, the alteration in expression level of serine/threonine kinase, mammalian target of rapamycin (mTOR), which is known to be associated with autophagic regulation,(26) was detected in HeLa cells. Because regulation of mTOR by the PI3K/Akt pathway has been revealed,(26) phosphorylation of PI3K/Akt-related proteins such as phospho-Akt and phospho-p70S6K were measured as well. Shown in Figure 3 are the phosphorylation levels of these proteins related to autophagy induction in HeLa cells at 24 h post-irradiation. Obviously, the protein expression level of phospho-mTOR decreased in HeLa cells irradiated with the carbon ions of 13 and 75 keV/μm. However, more reduction in the expression level was observed in HeLa cells after exposure to the carbon ions of 75 keV/μm than to those of 13 keV/μm. Compared with the unirradiated control cells, the phospho-mTOR level reduced to approximately 50% and 29% in the cells exposed to the carbon ions of 13 and 75 keV/μm at 24 h post-irradiation, respectively (Fig. 3b). As expected, phosphorylation of the PI3K/Akt-related proteins were effectively depressed by the carbon ion irradiations. The cellular contents of phospho-Akt and phospho-p70S6K proteins in HeLa cells irradiated with the relatively low LET carbon ions reduced to 90% and 68% of the corresponding amounts in the unirradiated cells, respectively, and to 24% and 15% in the cells irradiated with the high-LET carbon ions (Fig. 3b). These results indicate that the carbon ion irradiations induced autophagy in HeLa cells by degrading the activation of the PI3K/Akt pathway, and this pathway was more effectively depressed by the carbon ions with high LET than relatively low LET.
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.