Article

Guo JY, Chen HY, Mathew R et al.Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460-470

The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
Genes & development (Impact Factor: 10.8). 02/2011; 25(5):460-70. DOI: 10.1101/gad.2016311
Source: PubMed

ABSTRACT

Autophagy is a catabolic pathway used by cells to support metabolism in response to starvation and to clear damaged proteins and organelles in response to stress. We report here that expression of a H-ras(V12) or K-ras(V12) oncogene up-regulates basal autophagy, which is required for tumor cell survival in starvation and in tumorigenesis. In Ras-expressing cells, defective autophagosome formation or cargo delivery causes accumulation of abnormal mitochondria and reduced oxygen consumption. Autophagy defects also lead to tricarboxylic acid (TCA) cycle metabolite and energy depletion in starvation. As mitochondria sustain viability of Ras-expressing cells in starvation, autophagy is required to maintain the pool of functional mitochondria necessary to support growth of Ras-driven tumors. Human cancer cell lines bearing activating mutations in Ras commonly have high levels of basal autophagy, and, in a subset of these, down-regulating the expression of essential autophagy proteins impaired cell growth. As cancers with Ras mutations have a poor prognosis, this "autophagy addiction" suggests that targeting autophagy and mitochondrial metabolism are valuable new approaches to treat these aggressive cancers.

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    • "Recent studies indeed disclose that aggressive tumors driven by activating Ras mutations (Easty et al., 2011; Ji et al., 2012), such as pancreatic and lung cancer, are particular reliant on autophagy to support energy metabolism, cell growth and viability in nutrient-deprived conditions (Guo et al., 2011; Lock et al., 2010; Ma et al., 2011; Yang et al., 2011). Using genetically engineered mouse models of KRas G12D -driven non-small cell lung carcinoma, the genetic ablation of autophagy was shown to convert aggressive adenomas and adenocarcinomas into benign tumors (oncocytomas). "
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    ABSTRACT: Autophagy, or self-eating, is the most extensively studied lysosomal degradation pathway for the recycling of obsolete or damaged cytoplasmic materials, including proteins and organelles. Although this pathway was initially thought to function as trafficking system for ‘in bulk’ degradation by the lysosomes of cytoplasmic material, it is now widely appreciated that cargo selection by the autophagic machinery is a major process underlying the cytoprotective or –possibly- pro-death functions ascribed to this catabolic process. Indeed increasing evidence suggests that in mammalian cells the removal of dysfunctional or aged mitochondria occurs through a selective degradation pathway known as ‘mitophagy’. Due to the crucial role of mitochondria in energy metabolism, redox control and cell survival/death decision, deregulated mitophagy can potentially impact a variety of crucial cell autonomous and non-autonomous processes. Accumulating evidence indicates that during malignant transformation aggressive cancers hijack autophagy to preserve energy fitness and to acquire the plasticity required to adapt to the hostile microenvironment. However, whether and how mitophagy contributes to carcinogenesis, which pathways regulates this process in the cancer cells and how cancer cell-mitophagy impacts and modifies the tumor microenvironment and therapeutic responses, remain largely unanswered issues. In this review, we discuss novel paradigms and pathways regulating mitophagy in mammalian cells and the impact this process might have on one of the most dreadful human malignancies, melanoma.
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    • "Interestingly, expression of K-Ras G12V encourages the formation of reactive oxygen species (ROS) and the activation of JNK in MCF10A cells, which mediates the upregulation of Atg5 and Atg7 and subsequently leads to autophagy induction. Similarly, introducing K- or H-Ras G12V into non-tumorigenic iBMK cells was reported to stimulate mTOR1 activation accompanied by higher levels of basal autophagy [45]. Therefore, in these cells, Ras induces autophagy despite mTOR1 activation. "
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    ABSTRACT: Autophagy, a process of self-degradation and turnover of cellular components, plays a complex role in cancer. Evidence exists to show that autophagy may support tumor growth and cell survival, whereas it can also contribute to tumor suppression and have anti-survival characteristics in different cellular systems. Numerous studies have described the effects of various oncogenes and tumor suppressors on autophagy. The small GTPase Ras is an oncogene involved in the regulation of various cell-signaling pathways, and is mutated in 33% of human cancers. In the present review, we discuss the interplay between Ras and autophagy in relation to oncogenesis. It appears that Ras can upregulate or downregulate autophagy through several signaling pathways. In turn, autophagy can affect the tumorigenicity driven by Ras, resulting in either tumor progression or repression, depending on the cellular context. Furthermore, Ras inhibitors were shown to induce autophagy in several cancer cell lines.
    Full-text · Article · Feb 2014 · Oncotarget
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    • "For example dysregulated balance between aerobic glycolytic activity and oxidative phosphorylation is observed (Guo et al., 2011; Lock et al., 2011; Yang et al., 2011). It is possible such metabolic alterations reflects problems caused by the inability of autophagy to participate in mitochondrial homeostasis (mitophagy) in these cells (Guo et al., 2011; Kim et al., 2011b; Yang et al., 2011) or by other yet to be determined mechanisms, either involving lysosomal degradative activity or otherwise. Overall these observations suggest that targeting of autophagy in KRAS mutant cancers might be beneficial, at least in some types and stages of cancer. "
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    ABSTRACT: The role of macroautophagy (hereafter autophagy) in cancer biology and response to clinical intervention is complex. It is clear that autophagy is dysregulated in a wide variety of tumor settings, both during tumor initiation and progression, and in response to therapy. However, the pleiotropic mechanistic roles of autophagy in controlling cell behavior make it difficult to predict in a given tumor setting what the role of autophagy, and, by extension, the therapeutic outcome of targeting autophagy, might be. In this review we summarize the evidence in the literature supporting pro- and anti-tumorigenic and -therapeutic roles of autophagy in cancer. This overview encompasses roles of autophagy in nutrient management, cell death, cell senescence, regulation of proteotoxic stress and cellular homeostasis, regulation of tumor-host interactions and participation in changes in metabolism. We also try to understand, where possible, the mechanistic bases of these roles for autophagy. We specifically expand on the emerging role of genetically-engineered mouse models of cancer in shedding light on these issues in vivo.We also consider how any or all of the above functions of autophagy proteins might be targetable by extant or future classes of pharmacologic agents. We conclude by briefly exploring non-canonical roles for subsets of the key autophagy proteins in cellular processes, and how these might impact upon cancer.
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