Induction of cellular prion protein (PrPc) under hypoxia inhibits apoptosis caused by TRAIL treatment

Park, Jin‐Young; Jeong, Jae‐Kyo; Moon, Ji-Hong; Kim, Sung-Wook; Lee, You-Jin; Park, Sang-Youel

doi:10.18632/oncotarget.3028

Cited by 19 publications

(21 citation statements)

References 48 publications

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“…Therapeutically, we provide experimental evidence that combinatorial treatment strategies with TRAIL and SMAC mimetics or XIAP-targeting drugs overcome the apoptosis-hampering conditions imposed by the hypoxic tumor microenvironment. Our findings extend previous approaches to overcome hypoxia-induced apoptosis resistance [29, 30] and also have a broad clinical applicability in colorectal cancer cells exhibiting TRAIL-resistance under normoxia.…”

Section: Discussionsupporting

confidence: 84%

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

et al. 2016

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The capacity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to selectively induce cell death in malignant cells triggered numerous attempts for therapeutic exploitation. In clinical trials, however, TRAIL did not live up to the expectations, as tumors exhibit high rates of TRAIL resistance in vivo. Response to anti-cancer therapy is determined not only by cancer cell intrinsic factors (e.g. oncogenic mutations), but also modulated by extrinsic factors such as the hypoxic tumor microenvironment.Here, we address the effect of hypoxia on pro-apoptotic TRAIL signaling in colorectal cancer cells. We show that oxygen levels modulate susceptibility to TRAIL-induced cell death, which is severely impaired under hypoxia (0.5% O2). Mechanistically, this is attributable to hypoxia-induced mitochondrial autophagy. Loss of mitochondria under hypoxia restricts the availability of mitochondria-derived pro-apoptotic molecules such as second mitochondria-derived activator of caspase (SMAC), thereby disrupting amplification of the apoptotic signal emanating from the TRAIL death receptors and efficiently blocking cell death in type-II cells. Moreover, we identify strategies to overcome TRAIL resistance in low oxygen environments. Counteracting hypoxia-induced loss of endogenous SMAC by exogenous substitution of SMAC mimetics fully restores TRAIL sensitivity in colorectal cancer cells. Alternatively, enforcing a mitochondria-independent type-I mode of cell death by targeting the type-II phenotype gatekeeper X-linked inhibitor of apoptosis protein (XIAP) is equally effective.Together, our results indicate that tumor hypoxia impairs TRAIL efficacy but this limitation can be overcome by combining TRAIL with SMAC mimetics or XIAP-targeting drugs. Our findings may help to exploit the potential of TRAIL in cancer therapy.

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Section: Discussionsupporting

confidence: 84%

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

et al. 2016

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“…Although the discovery of factors that cause CRC give new insights into the growth and metastasis of CRC, there is still little information on the etiology of most CRC, therapeutic agents, and anti-CRC targeting molecules. However, cellular prion protein (PrP c ) expression has been identified as a risk or susceptibility factor for developing CRC (17). In essence, PrP c is a highly conserved cell-surface glycoprotein that has been identified in all vertebrates, with the same protein sequence as the prion proteins that cause scrapies in sheep, bovine spongiform encephalopathy in cattle, and kuru in human beings (18,19).…”

Section: Furthermore We Provide Evidence For the Therapeutic Applicamentioning

confidence: 99%

Silencing Prion Protein in HT29 Human Colorectal Cancer Cells Enhances Anticancer Response to Fucoidan

Yun

Lee

et al. 2016

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Developing natural products and dietary supplements has proven to be a promising strategy for the cancer therapy and prevention. Among them, fucoidan, which is isolated from brown seaweed such as Cladosiphon okamuranus and Fucus evanescens (1, 2), is structurally similar to heparin, with a substantial percentage of L-fucose (3, 4). Recent studies have shown its various effects on biological activities such as antiinflammatory, anti-coagulant (5), anti-HIV, and anticancer (6-9) activities. With respect to cancer therapy, fucoidan appears to be highly efficient in treating certain types of cancer, including breast, prostate and lung, as well as leukemia (10-12). Furthermore, fucoidan can also play a crucial role in inhibiting induced cancer signaling molecules, such as vascular endothelial growth factor (VEGF) (13,14). Although these results support the potential development of fucoidan as an anticancer drug, there is little information on the anticancer effect of fucoidan on colorectal cancer (CRC).CRC is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite continuous progress in developing diagnostic and therapeutic methods (15). It is thought that CRC may be caused by a combination of both genetic susceptibilities and Iifestyle factors such as a meat-rich diet (16). Although the discovery of factors that cause CRC give new insights into the growth and metastasis of CRC, there is still little information on the etiology of most CRC, therapeutic agents, and anti-CRC targeting molecules. However, cellular prion protein (PrP c ) expression has been identified as a risk or susceptibility factor for developing CRC (17). In essence, PrP c is a highly conserved cell-surface glycoprotein that has been identified in all vertebrates, with the same protein sequence as the prion proteins that cause 4449

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“…As previously mentioned, PrP C also is regulated by HIF, and PrP C expression is increased under hypoxic conditions. Park et al ( 3 ) demonstrated that the effects of HIF-1α and PrP C on neuronal cell death are prion peptide-induced. In hypoxic conditions, neurons are protected from PrP-induced cell death via the activation of p65 and HIF-1α and subsequent inactivation of p21 and p53 signals.…”

Section: Hif-1α Regulates Prp Cmentioning

confidence: 99%

“…For these reasons, recent research has focused on obtaining more conclusive information about the functional role of PrP C in tissue regeneration. Additionally, regulating PrP C expression by hypoxia has become an important topic ( 3 ). Hypoxia occurs when blood oxygen concentrations are insufficient and long periods of hypoxia can induce cell death.…”

Section: Introductionmentioning

confidence: 99%

Role of hypoxia-mediated cellular prion protein functional change in stem cells and potential application in angiogenesis

Yun

Han

Lee

et al. 2017

Molecular Medicine Reports

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Cellular prion protein (PrPC) can replace other pivotal molecules due to its interaction with several partners in performing a variety of important biological functions that may differ between embryonic and mature stem cells. Recent studies have revealed major advances in elucidating the putative role of PrPC in the regulation of stem cells and its application in stem cell therapy. What is special about PrPC is that its expression may be regulated by hypoxia-inducible factor (HIF)-1α, which is the transcriptional factor of cellular response to hypoxia. Hypoxic conditions have been known to drive cellular responses that can enhance cell survival, differentiation and angiogenesis through adaptive processes. Our group recently reported hypoxia-enhanced vascular repair of endothelial colony-forming cells on ischemic injury. Hypoxia-induced AKT/signal transducer and activator of transcription 3 phosphorylation eventually increases neovasculogenesis. In stem cell biology, hypoxia promotes the expression of growth factors. According to other studies, aspects of tissue regeneration and cell function are influenced by hypoxia, which serves an essential role in stem cell HIF-1α signaling. All these data suggest the possibility that hypoxia-mediated PrPC serves an important role in angiogenesis. Therefore, the present review summarizes the characteristics of PrPC, which is produced by HIF-1α in hypoxia, as it relates to angiogenesis.

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Induction of cellular prion protein (PrPc) under hypoxia inhibits apoptosis caused by TRAIL treatment

Cited by 19 publications

References 48 publications

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

Silencing Prion Protein in HT29 Human Colorectal Cancer Cells Enhances Anticancer Response to Fucoidan

Role of hypoxia-mediated cellular prion protein functional change in stem cells and potential application in angiogenesis

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