Abstract：
:Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated β-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated β-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Nam HY,Han MW,Chang HW,Lee YS,Lee M,Lee HJ,Lee BW,Lee HJ,Lee KE,Jung MK,Jeon H,Choi SH,Park NH,Kim SY,Kim SWdoi
10.1158/0008-5472.CAN-12-3516subject
Has Abstractpub_date
2013-07-15 00:00:00pages
4267-77issue
14eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-12-3516journal_volume
73pub_type
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