Molecular mechanisms of mTOR regulation by stress.
Tumors are prime examples of cell growth in unfavorable environments that elicit cellular stress. The high metabolic demand and insufficient vascularization of tumors cause a deficiency of oxygen and nutrients. Oncogenic mutations map to signaling events via mammalian target of rapamycin (mTOR), metabolic pathways, and mitochondrial function. These alterations have been linked with cellular stresses, in particular endoplasmic reticulum (ER) stress, hypoxia, and oxidative stress. Yet tumors survive these challenges and acquire highly energy-demanding traits, such as overgrowth and invasiveness. In this review we focus on stresses that occur in cancer cells and discuss them in the context of mTOR signaling. Of note, many tumor traits require mTOR complex 1 (mTORC1) activity, but mTORC1 hyperactivation eventually sensitizes cells to apoptosis. Thus, mTORC1 activity needs to be balanced in cancer cells. We provide an overview of the mechanisms contributing to mTOR regulation by stress and suggest a model wherein stress granules function as guardians of mTORC1 signaling, allowing cancer cells to escape stress-induced cell death.
Department of Pediatrics and Centre for Systems Biology of Energy Metabolism and Ageing; University of Groningen ; University Medical Center Groningen (UMCG); Groningen , The Netherlands.
Alexander Martin
AM
Heberle
Department of Pediatrics and Centre for Systems Biology of Energy Metabolism and Ageing; University of Groningen; University Medical Center Groningen (UMCG); Groningen, The Netherlands; Faculty of Biology; Institute for Biology 3; Albert-Ludwigs-University Freiburg; Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM); University of Freiburg; Freiburg, Germany.
Mirja Tamara
MT
Prentzell
Department of Pediatrics and Centre for Systems Biology of Energy Metabolism and Ageing; University of Groningen; University Medical Center Groningen (UMCG); Groningen, The Netherlands; Top Institute Food and Nutrition; Wageningen, The Netherlands.
Karen
K
van Eunen
Department of Pediatrics and Centre for Systems Biology of Energy Metabolism and Ageing; University of Groningen ; University Medical Center Groningen (UMCG); Groningen , The Netherlands.
Barbara Marleen
BM
Bakker
School of Biological and Biomedical Sciences; Durham University ; Durham , UK.
Sushma Nagaraja
SN
Grellscheid
Department of Pediatrics and Centre for Systems Biology of Energy Metabolism and Ageing; University of Groningen; University Medical Center Groningen (UMCG); Groningen, The Netherlands; Faculty of Biology; Institute for Biology 3; Albert-Ludwigs-University Freiburg; Freiburg, Germany; School of Medicine and Health Sciences; Carl von Ossietzky University Oldenburg; Oldenburg, Germany; BIOSS Centre for Biological Signaling Studies; Albert-Ludwigs-University Freiburg; Freiburg, Germany.
Kathrin
K
Thedieck
ER stress; RNA granules; apoptosis; balance; cancer; cell death; hyperactivation; hypoxia; mTORC1; mTORC2; mammalian target of rapamycin; oxidative stress; stress granules; survival