Interplay between autophagy and metabolism in Ras mutation-induced tumorigenesis.

M acroautophagy (hereafter referred to as autophagy) or ‘self-eating’ is a lysosomal degradation pathway and plays a role in the breakdown of disordered intracellular organelles, such as peroxisomes (pexophagy), mitochondria (mitophagy), endoplasmic reticula (reticulophagy) and ribosomes (ribophagy), as well as providing for controlled recycling of macromolecules during cellular adaption and pathogenesis. Mitophagy serves to remove mitochondria containing damaged components and also to eliminate subsets of mitochondria producing reactive oxygen species. The lysosomal compartment is responsible for the controlled recycling of cellular organelles and macromolecules. These dynamic organelles contain hydrolytic enzymes (proteases, lipases and glycosidases) capable of degrading proteins, proteoglycans, nucleic acids and lipids. Both heterophagic and autophagic cargos find their final destiny in lysosomes, where they are broken down by numerous hydrolyses. Certain environmental cues (such as starvation, high temperature, low oxygen and hormonal stimulation) or intracellular stress (damaged organelles, accumulation of mutant proteins and microbial invasion) activate signaling pathways that increase autophagy. When the cell receives an appropriate signal, autophagyexecution proteins trigger a cascade of reactions that result in the formation of double membrane-bound vesicles called autophagosomes. The vesicles then fuse with lysosomes followed by a release of lysosomal digestive enzymes into the lumen of the resulting autolysosomes. The sequestered cytoplasmic contents are degraded inside the autolysosome into free nucleotides, amino acids and fatty acids, which are reused by the cell to maintain macromolecular synthesis and to fuel energy production. Autophagy is induced in vivo in tumors in hypoxic regions and contributes to tumor cell survival. Accumulated defective lysosomes and autophagic vacuoles were detected in both nuclear receptor PPARcand PPARc2-deficient prostatic carcinogenesis. Autophagy is also frequently activated in different tumor cells treated with chemotherapy or irradiation. Short-term inhibition of autophagy along with radiotherapy leads to enhanced cytotoxicity of radiotherapy in resistant cancer cells. Autophagy acts either to destroy defective cells, or as a survival mechanism for damaged cells putting them in a position to accumulate further genetic damage, suggestive of ‘a doubleedged of sword’ reported in different types of cancer. Whether autophagy is ‘protective’ for the organism by promoting effective ‘self-eating and self-digesting’ and/or ‘self-killing’ of damaged cells or alternatively, acts as an ‘oncogenic’ survival response in cancer is not yet determined. Recently in an original research paper published in Genes & Development, Guo et al. hypothesized that autophagy plays opposing roles in tumor initiation and in established human tumors. They suggested that, whereas damage mitigation resulting from autophagy may be important for suppressing tumor initiation, in aggressive cancers, growth in a stressed microenvironment may instead result in dependency on autophagy for survival. The intriguing work reported by Guo et al. impacts on the interplay between autophagy/mitophagy and mitochondrially oxidative metabolism in a model of Ras mutations (H-ras or K-ras)-induced tumorigenesis. The authors have established an integrated in vitro and in vivo system to investigate the biological functions of autophagy in maintaining oxidative metabolism in active Ras-mediated tumorigenesis. Guo et al. first delineated the functional roles and biopathological consequences of active autophagy in Ras mutation-mediated tumorigenesis. Using an immortal non-tumorigenic baby mouse kidney epithelial line iBMK, they tested the hypothesis that activation of a strong cell growth-promoting oncogene such as Hras or K-ras would alter the requirement for autophagy. They found that isogenic iBMK cell lines deficient for the essential autophagy genes atg5 or atg7 are completely defective for autophagy. Interestingly, allelic loss of the essential autophagy gene beclin1 produces a partial autophagy defect. Activated Rasexpressing iBMK cells are dependent on autophagy creating ‘autophagy addiction’ to survive starvation involving elevated p62 (an autophagy cargo receptor) expression. They demonstrated that autophagy supports activated Ras-mediated tumorigenesis in iBMK cells. The authors also detected a high level of basal autophagy in a number of human cancer cell lines with Ras mutations and determined that autophagy facilitates growth and survival of a subset of human cancer cell lines with active Ras. Then, Guo et al. investigated the mechanism of interactions between autophagy and oxidative metabolism to support cancer cell survival. They found that Ras-expressing isogenic iBMK tumors (atg5, atg7, beclin1 and p62) showed a striking accumulation of abnormal, swollen mitochondria consistent with defective mitophagy. These cells displayed autophagy defects and impaired mitochondrial function, maintenance of mitochondrial membrane potential, mitochondrial respiration and oxygen consumption. Autophagy deficiency depletes mitochondrially produced tricarboxylic acid cycle metabolites, likely by impairing mitochondrial conversion of pyruvate and/or fatty acid into acetyl-CoA and citrate under Ras expression. Finally, Guo et al. found that in autophagy-defective cells, the metabolic insufficiency in starvation produces an acute energy crisis, leading to cell death and suggested that development of specific autophagy inhibitors Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA Correspondence: Dr M Jiang ([email protected]) Asian Journal of Andrology (2011) 13, 610–611 2011 AJA, SIMM & SJTU. All rights reserved 1008-682X/11 $32.00