Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

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 b-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 b-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. Cancer Res; 73(14); 4267-77. Ó2013 AACR.

Influence of autophagy on the efficacy of radiotherapy

“…During this period, the senescence-associated β-galactosidase activity also showed that premature senescence has been initiated, caused by the inhibition of mechanistic target of rapamycin (mTOR) pathway. Similar results have also been obtained in tumour xenografts [8]. …”

Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

“…Additionally, senescence induced by hyperactivation of Akt was mediated through mTORC1, although details regarding the involvement of autophagy in this mechanism need to be elucidated [23]. Moreover, it was observed that combining autophagy inhibitors with radiation treatment could trigger premature senescence in both cancer cells and xenograft models, which is an approach to restoring radiosensitivity [24].…”

The Effect of Radiation on the Immune Response to Cancers

“…This radiation-enhancing effect seems to result from heterochromatin remodeling, irreversible growth arrest, and premature senescence. At the cellular level, enhanced radiosensitivity is likely due to the restoration in tumor suppressor RB1 activity and its subsequent suppression of E2F transcription factor 1 (E2F1) activity [3,4]. For prostate cancer, which is considered relatively radio-resistant, treatment with the phorbol ester, 12- O -tetradecanoylphorbol 12-acetate (TPA), can also enhance radiation-induced cytotoxicity.…”