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      Role of tumor and host autophagy in cancer metabolism

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      Genes & Development

      Cold Spring Harbor Laboratory

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          Pancreatic cancers require autophagy for tumor growth.

          Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
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            Protein turnover via autophagy: implications for metabolism.

            Autophagy is a process of cellular "self-eating" in which portions of cytoplasm are sequestered within double-membrane cytosolic vesicles termed autophagosomes. The autophagosome cargo is delivered to the lysosome, broken down, and the resulting amino acids recycled after release back into the cytosol. Autophagy occurs in all eukaryotes and can be up-regulated in response to various nutrient limitations. Under these conditions, autophagy may become essential for viability. In addition, autophagy plays a role in certain diseases, acting to prevent some types of neurodegeneration and cancer, and in the elimination of invading pathogens. We review the current information on the mechanism of autophagy, with a focus on its role in protein metabolism and intracellular homeostasis.
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              Mitochondria and Cancer.

              Decades ago, Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events that drive aberrant cancer cell proliferation also alter biochemical metabolism, including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy; provide building blocks for new cells; and control redox homeostasis, oncogenic signaling, innate immunity, and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mtDNA limits tumorigenesis, and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multifunctional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.
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                Author and article information

                Journal
                Genes & Development
                Genes Dev.
                Cold Spring Harbor Laboratory
                0890-9369
                1549-5477
                June 03 2019
                June 01 2019
                June 03 2019
                June 01 2019
                : 33
                : 11-12
                : 610-619
                Article
                10.1101/gad.325514.119
                © 2019

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