Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia

Endo, Hideki; Okuyama, Hiroaki; Ohue, Masayuki; Inoue, Masahiro

doi:10.1371/journal.pone.0098858

Cited by 51 publications

(49 citation statements)

References 39 publications

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“…Additionally, chronic hypoxia has also shown to suppress Akt activation in hypoxia-treated PC cells. 29 Similarly, we also observed that levels of phosphorylated Akt and mTORC1 effector, pS6 kinase, were consistently reduced in hypoxia-treated PC cells, whereas expression of EGFR, pEGFR, Akt and S6 kinase remained unchanged (Figure 5a). We observed significant reduction in p53 expression in hypoxia-treated cells lines, suggesting the possible accumulation of genomic and cellular defects in stressed PC cells.…”

Section: Resultssupporting

confidence: 66%

Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival

et al. 2016

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Pancreatic cancer (PC) and associated pre-neoplastic lesions have been reported to be hypoxic, primarily due to hypovascular nature of PC. Though the presence of hypoxia under cancerous condition has been associated with the overexpression of oncogenic proteins (MUC1), multiple emerging reports have also indicated the growth inhibitory effects of hypoxia. In spite of being recognized as the top-most differentially expressed and established oncogenic protein in PC, MUC4 regulation in terms of micro-environmental stress has not been determined. Herein, for the first time, we are reporting that MUC4 protein stability is drastically affected in PC, under hypoxic condition in a hypoxia inducible factor 1α (HIF-1α)-independent manner. Mechanistically, we have demonstrated that hypoxia-mediated induction of reactive oxygen species (ROS) promotes autophagy by inhibiting pAkt/ mTORC1 pathway, one of the central regulators of autophagy. Immunohistofluorescence analyses revealed significant negative correlation (P-value = 0.017) between 8-hydroxy guanosine (8-OHG) and MUC4 in primary pancreatic tumors (n = 25). Moreover, we found pronounced colocalization between MUC4 and LAMP1/LC3 (microtubule-associated protein 1A/1B-light chain 3) in PC tissues and also observed their negative relationship in their expression pattern, suggesting that areas with high autophagy rate had less MUC4 expression. We also found that hypoxia and ROS have negative impact on overall cell growth and viability, which was partially, though significantly (P < 0.05), rescued in the presence of MUC4. Altogether, hypoxia-mediated oxidative stress induces autophagy in PC, leading to the MUC4 degradation to enhance survival, possibly by offering required metabolites to stressed cells.

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Section: Resultssupporting

confidence: 66%

Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival

et al. 2016

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“…Interestingly, these regions still express the HIF1 target HIGD1A. One way that cells can survive metabolic stress is via lowering cellular ROS and oxygen consumption, which are parameters associated with quiescence and dormancy-mediated survival (Endo et al, 2014; Lagadinou et al, 2013; Lopes et al, 2010). Consistent with this, we found that HIGD1A interacts with the mitochondrial electron transport chain, modulates oxygen consumption, ROS production and AMPK activity to promote cell survival during glucose starvation, while simultaneously suppressing tumor growth in vivo .…”

Section: Discussionmentioning

confidence: 99%

HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

Ameri¹,

Jahangiri²,

Rajah³

et al. 2015

Cell Reports

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Hypoxia-Inducible Gene Domain Family Member 1A (HIGD1A) is a survival factor induced by Hypoxia-inducible Factor-1 (HIF1). HIF1 regulates many responses to oxygen deprivation but viable cells within hypoxic perinecrotic solid tumor regions frequently lack HIF1α. HIGD1A is induced in these HIF-deficient extreme environments and interacts with the mitochondrial electron transport chain to repress oxygen consumption, enhance AMPK activity and lower cellular ROS levels. Importantly, HIGD1A decreases tumor growth but promotes tumor cell survival in vivo. The human Higd1a gene is located on chromosome 3p22.1, where many tumor suppressor genes reside. Consistent with this, the Higd1a gene promoter is differentially methylated in human cancers, preventing its hypoxic induction. When hypoxic tumor cells are confronted with glucose deprivation, however, DNA methyltransferase activity is inhibited, enabling HIGD1A expression, metabolic adaptation and possible dormancy induction. Our findings therefore reveal important new roles for this family of mitochondrial proteins in cancer biology.

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“…Interestingly, it has been shown that cancer cells with mutations that constitutively activate the PI(3)K-AKT axis can still downregulate this pathway upon entering a quiescent state, for example, through ubiquitin-mediated degradation (58,66,67). The fact that mechanisms exist to abrogate supposed driver pathway of mutagenesis argues for the hypothesis that cellular dormancy offers an evolutionary advantage towards tumor progression.…”

Section: Cellular Dormancy At a Molecular And Cellular Levelmentioning

confidence: 99%

Mechanisms of Cancer Cell Dormancy—Another Hallmark of Cancer?

2015

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Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biological level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biological insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately down-regulate the Ras/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance.

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Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia

Cited by 51 publications

References 39 publications

Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival

Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival

HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

Mechanisms of Cancer Cell Dormancy—Another Hallmark of Cancer?

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