Involvement of mitophagy in oncogenic K-Ras-induced transformation

Kim, June Hyung; Kim, Hee Young; Lee, Young Kyoung; Yoon, Younju; Xu, Wei; Yoon, Joon Kee; Choi, Sung Eun; Ko, Young Gyu; Kim, Min Jung; Lee, Su Jae; Wang, Hee Jung; Yoon, Gyesoon

doi:10.4161/auto.7.10.16643

Cited by 95 publications

(40 citation statements)

References 49 publications

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“…Therefore, autophagy-dependent degradation of unnecessary mitochondria may serve as a useful mechanism to resupply nutrients and expedite glycolysis. This hypothesis is well supported by recent reports that autophagy facilitates glycolysis; 101 hence, transformed cells maintain small numbers of mitochondria during periods of rapid proliferation 102 . Further support in favor of this hypothesis comes from electron microscopy images which show a decreased number of intracellular organelles within the cytosol of proliferating cancer cells.…”

Section: General Aspects Of the Unfolded Protein Responsesupporting

confidence: 61%

“…Further support in favor of this hypothesis comes from electron microscopy images which show a decreased number of intracellular organelles within the cytosol of proliferating cancer cells. This could mean that cancer cells may activate autophagy-mediated organelle degradation to maintain cellular ATP levels and resupply nutrients when glucose levels are insufficient 102 . Selective autophagy is also a backup mechanism for the failed proteasomal degradation of ubiquitinated aggregation-prone and misfolded proteins.…”

Section: General Aspects Of the Unfolded Protein Responsementioning

confidence: 99%

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New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

et al. 2017

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Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.

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Section: General Aspects Of the Unfolded Protein Responsesupporting

confidence: 61%

Section: General Aspects Of the Unfolded Protein Responsementioning

confidence: 99%

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

et al. 2017

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“…Indeed, removal of mitochondria by autophagy in cellular models of senescence [27] and during erythrocyte maturation [28] has been shown to trigger a glycolytic phenotype. This phenomenon has also been observed in cell models of K-Ras transformation where autophagic depletion of mitochondria results in increased glycolysis and decreased oxygen consumption which was rescued by pharmacological inhibition of autophagy [29]. In this work, we observe a reduction in TOM20 staining following ARHI induction (Fig.…”

Section: Discussionsupporting

confidence: 82%

Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models

et al. 2016

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BackgroundAutophagy is a bulk catabolic process that modulates tumorigenesis, therapeutic resistance, and dormancy. The tumor suppressor ARHI (DIRAS3) is a potent inducer of autophagy and its expression results in necroptotic cell death in vitro and tumor dormancy in vivo. ARHI is down-regulated or lost in over 60 % of primary ovarian tumors yet is dramatically up-regulated in metastatic disease. The metabolic changes that occur during ARHI induction and their role in modulating death and dormancy are unknown.MethodsWe employed Nuclear Magnetic Resonance (NMR)-based metabolomic strategies to characterize changes in key metabolic pathways in both cell culture and xenograft models of ARHI expression and autophagy. These pathways were further interrogated by cell-based immunofluorescence imaging, tracer uptake studies, targeted metabolic inhibition, and in vivo PET/CT imaging.ResultsInduction of ARHI in cell culture models resulted in an autophagy-dependent increase in lactate production along with increased glucose uptake and enhanced sensitivity to glycolytic inhibitors. Increased uptake of glutamine was also dependent on autophagy and dramatically sensitized cultured ARHI-expressing ovarian cancer cell lines to glutaminase inhibition. Induction of ARHI resulted in a reduction in mitochondrial respiration, decreased mitochondrial membrane potential, and decreased Tom20 staining suggesting an ARHI-dependent loss of mitochondrial function. ARHI induction in mouse xenograft models resulted in an increase in free amino acids, a transient increase in [18F]-FDG uptake, and significantly altered choline metabolism.ConclusionsARHI expression has previously been shown to trigger autophagy-associated necroptosis in cell culture. In this study, we have demonstrated that ARHI expression results in decreased cellular ATP/ADP, increased oxidative stress, and decreased mitochondrial function. While this bioenergetic shock is consistent with programmed necrosis, our data indicates that the accompanying up-regulation of glycolysis and glutaminolysis is autophagy-dependent and serves to support cell viability rather than facilitate necroptotic cell death. While the mechanistic basis for metabolic up-regulation following ARHI induction is unknown, our preliminary data suggest that decreased mitochondrial function and increased metabolic demand may play a role. These alterations in fundamental metabolic pathways during autophagy-associated necroptosis may provide the basis for new therapeutic strategies for the treatment of dormant ovarian tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2850-8) contains supplementary material, which is available to authorized users.

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“…However, like autophagy, mitophagy may have context-dependent roles in cancer. For example, mitophagy maintains the pool of functional mitochondria necessary to support growth of Ras-driven tumours [13, 24], while Ras-induced autophagy can mediate the functional loss of mitochondria during transformation [25]. In this regard, it is intriguing that STK38 can act in mitochondrial quality control [45] in addition to its role in non-selective autophagy [29].…”

Section: Resultsmentioning

confidence: 99%

“…However, we currently do not fully understand whether the inhibition of a specific type of autophagy is sufficient to impair the survival of Ras-transformed cells. For example, it was reported that mitophagy, a selective autophagic processes targeting specifically mitochondria [21–23], can maintain the pool of functional mitochondria necessary to support growth of Ras-driven tumours [13, 24], while Ras-induced autophagy can mediate the functional loss of mitochondria during transformation [25]. Thus, the role of mitophagy in Ras-transformed human cells is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation

et al. 2016

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Oncogenic Ras signalling occurs frequently in many human cancers. However, no effective targeted therapies are currently available to treat patients suffering from Ras-driven tumours. Therefore, it is imperative to identify downstream effectors of Ras signalling that potentially represent promising new therapeutic options. Particularly, considering that autophagy inhibition can impair the survival of Ras-transformed cells in tissue culture and mouse models, an understanding of factors regulating the balance between autophagy and apoptosis in Ras-transformed human cells is needed. Here, we report critical roles of the STK38 protein kinase in oncogenic Ras transformation. STK38 knockdown impaired anoikis resistance, anchorage-independent soft agar growth, and in vivo xenograft growth of Ras-transformed human cells. Mechanistically, STK38 supports Ras-driven transformation through promoting detachment-induced autophagy. Even more importantly, upon cell detachment STK38 is required to sustain the removal of damaged mitochondria by mitophagy, a selective autophagic process, to prevent excessive mitochondrial reactive oxygen species production that can negatively affect cancer cell survival. Significantly, knockdown of PINK1 or Parkin, two positive regulators of mitophagy, also impaired anoikis resistance and anchorage-independent growth of Ras-transformed human cells, while knockdown of USP30, a negative regulator of PINK1/Parkin-mediated mitophagy, restored anchorage-independent growth of STK38-depleted Ras-transformed human cells. Therefore, our findings collectively reveal novel molecular players that determine whether Ras-transformed human cells die or survive upon cell detachment, which potentially could be exploited for the development of novel strategies to target Ras-transformed cells.

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Involvement of mitophagy in oncogenic K-Ras-induced transformation

Cited by 95 publications

References 49 publications

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models

Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation

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