mTOR Inhibition Prevents Epithelial Stem Cell Senescence and Protects from Radiation-Induced Mucositis

Abstract

SUMMARY The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…These results indicate that despite lower mitochondrial content in hepatocytes, mitochondrial function is not significantly altered by mTORC1 inhibition. Recently, it has been suggested that rapamycin may reduce ROS generation via enhanced expression of the antioxidant enzyme MnSOD (Iglesias‐Bartolome et al , 2012), however, we failed to find any changes in MnSOD expression on rapamycin‐fed mice liver tissues (Appendix Fig S3C). …”

mTOR pathway activation drives lung cell senescence and emphysema

“…Concomitantly, exposure to oxidative stress due to cigarette smoke and chronic inflammation may promote premature cell senescence (5,33). Consistent with this possibility, mTOR was required for oxidative stress-induced cell senescence to occur (17,34), and mTOR activation was associated with oxidative stress in peripheral blood mononuclear cells from patients with COPD (35,36). Previous studies also documented a role of oxidative stress and mTOR activation in response to cigarette smoke exposure (37), and some effects of rapamycin on cell senescence have been related to changes in oxidative stress (17).…”

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

“…Despite this wealth of in vitro data, relatively little is known about the in vivo requirement of actomyosin contractility for desmosomal adhesion and epidermal barrier formation. mTOR signaling perturbation in the epidermis has previously been associated with epithelial carcinogenesis (30), epidermal stem cell senescence (31,32), and delayed wound healing (33). While this article was in preparation, an additional study demonstrated that mTOR kinase and mTORC1 loss of function is associated with impaired epidermal differentiation and barrier formation; however, the molecular mechanism of this finding was not elucidated, and no effects on cell-cell adhesion were described (34).…”