Hypoxia and Nitric Oxide Treatment Confer Tolerance to Glucose Starvation in a 5′-AMP-activated Protein Kinase-dependent Manner

Esumi, H.; Izuishi, Kunihiko; Kato, Kazúo; Hashimoto, Kouichi; Kurashima, Yukiko; Kishimoto, Atsuhiro; Ogura, Tsutomu; Ozawa, Takayuki

doi:10.1074/jbc.m112270200

Cited by 78 publications

(81 citation statements)

References 25 publications

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“…They were efficiently expressed (Figure 2b). ARK5 belongs to the AMPK catalytic subunit family (Suzuki et al, 2003a); therefore, we also examined the efficacy of antisense RNA expression vector of AMPK-a1 (AMPK-a1/AS and Esumi et al, 2002;Kato et al, 2002). As shown in Figure 2c, an introduction of AMPK-a1/AS into SW480 cells showed a dramatic To examine whether ARK5 promotes cell survival against Fas-mediated cell death, the effect of ARK5 overexpression was investigated.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, Akt which is a serine/threonine protein kinase induces cell survival as a result of phosphorylation and several cell death-associated factors, such as Bad (Datta et al, 1997;Peso et al, 1997), caspase-9 (Cardone et al, 1998) and Forkhead , upon the stimulation of growth factor receptor and integrin-induced cell signaling (Datta et al, 1999;Brazil et al, 2002). Furthermore, we recently demonstrated that members of AMPK catalytic subunit family play a major role in tumor cell survival during nutrient starvation and tumorigenesis (Izuishi et al, 2000;Esumi et al, 2002;Hashimoto et al, 2002;Kato et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of caspase-6 and FLIP by the AMPK family member ARK5

et al. 2004

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Colorectal cancer cells are unique in that they escape Fasmediated cell death in the presence of Fas ligand, and we recently reported that AMP-activated protein kinaserelated kinase 5 (ARK5) suppresses cell death signaling mediated by cell death receptor in Akt-dependent manner. In the current study, therefore, we examined whether ARK5 is involved in the escape from Fas-mediated cell death of colorectal cancer cells. Among 10 cell lines, ARK5 mRNA expression was observed in LoVo, SW480, and SW1116 cell lines. Interestingly, SW480 and SW1116 cell lines, but not LoVo cell line, showed expressions of both Fas ligand (FasL) and Fas mRNAs. SW620 cell line also showed FasL mRNA; however, Fas and ARK5 mRNAs were not detected. Furthermore, wellcoincided expression among ARK5, FasL, and Fas mRNAs was observed in tumor tissues from patients with colorectal cancer, suggesting the suppression of FasL/Fas system-induced cell death by ARK5 in colorectal cancer cell lines. Intensive cell death, which was dependent on the FasL/Fas system was encountered when ARK5 antisense RNA (ARK5/AS) was introduced into SW480 cells. FLIP was expressed in only ARK5 mRNA-expressing cell lines, and ARK5/AS induced FLIP cleavage in a caspase-6-dependent manner. Amino-acid sequence analysis of caspase-6 revealed two putative sites of phosphorylation by ARK5 at Ser 80 and Ser 257 . Although active caspase-6 overexpression induced cell death in SW480 and DLD-1 cell lines, SW480 cells, but not DLD-1 cells, exhibited strong resistance to procaspase-6 overexpression. Moreover, mutant caspase-6, in which the Ser 257 was substituted by Ala (caspase-6/SA), induced cell death and FLIP degradation, even in SW480 cells. Active ARK5 was found to phosphorylate wild-type caspase-6 in vitro, but not caspase-6/SA, and the prevented activation of caspase-6 was promoted due to its phosphorylation by active ARK5 in vitro. On the basis of the results of this study, we propose that ARK5 negatively regulates procaspase-6 by phosphorylation at Ser 257 , leading to resistance to the FasL/Fas system.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of caspase-6 and FLIP by the AMPK family member ARK5

et al. 2004

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“…Similar constitutive tolerance to nutrient deprivation has been observed in some poorly differentiated cancer cell lines, including pancreatic cancers, in which hypovascularity is commonly observed. 9,10,12) Based on our observations we hypothesized that the cancer cells might have acquired the ability to survive in an extremely adverse microenvironment not only through increased angiogenesis, but also by acquiring tolerance to nutrient starvation, i.e., by austerity. 10) Based on these observations, we developed a screening method for compounds that might provide the basis for an antiausterity strategy and identified kigamicin D, which has a novel structure and exhibits preferential cytotoxicity during nutrient starvation.…”

Section: Discussionmentioning

confidence: 99%

“…We therefore speculated that if some compound could abolish cancer cells' tolerance of nutrient starvation, it might be capable of being used to sensitize cancer cells to this hostile environment, resulting in repression of cancer by a new strategy that we termed "anti-austerity." 12) In this study, through screening over 2000 culture media of actinomycetes, we identified a new compound, kigamicin D, a polycyclic xanthone having sugar moieties and a molecular formula of C 48 H 59 NO 19 , as a candidate for this strategy. The possible mode of action of kigamicin D was also investigated.…”

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confidence: 99%

Kigamicin D, a novel anticancer agent based on a new anti‐austerity strategy targeting cancer cells' tolerance to nutrient starvation

et al. 2004

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Both tolerance to nutrient starvation and angiogenesis are essential for cancer progression because of the insufficient supply of nutrients to tumor tissue. Since chronic nutrient starvation seldom occurs in normal tissue, cancer's tolerance to nutrient starvation should provide a novel target for cancer therapy. In this study, we propose an anti-austerity strategy to exploit the ability of agents to eliminate cancer cells' tolerance to nutrient starvation. We established a simple screening method for agents that inhibit cancer cell viability preferentially during nutrient starvation, using PANC-1 cell line cultured in nutrient-rich and nutrientdeprived media. ancers always have deformed, deficient vascular and lymphatic systems due to excessive and unregulated tumor cell growth, as well as improper and insufficient angiogenesis. As a result, perfusion within cancers is inadequate, and the cancers contain regions that are transiently and chronically exposed to nutrient starvation. 1) These microenvironmental inadequacies are present from the earliest stage in the development of cancers, and are fully established while the neoplasm is still microscopic in size. 2) Since nutrient starvation occurs in tumor tissue that is >100-200 µm away from a functional blood supply, 3) tumor survival depends, in part, on the ability to recruit new blood microvessels via angiogenic factors. This affords tumor cells the ability to survive and propagate in a hostile environment, 4) and thus increased angiogenesis by a malignancy is related to a poor prognosis. 5,6) Because of this, antiangiogenic therapy was postulated to be the most promising and specific approach to cancer therapy. Already, extensive studies have been conducted in an attempt to prevent tumor angiogenesis.However, Yu et al. recently suggested that tumors may be able to elude the effect of angiogenesis inhibitors, since antiangiogenic therapy targets genetically stable endothelial cells in the tumor vasculature, and genetic alterations that decrease the vascular dependence of tumor cells can influence the response of tumors to this therapy. 7) The well-known observation that hypovascularity is an outstanding characteristic of pancreatic cancers in diagnostic images suggests that pancreatic cancer tissue has a poor blood supply. 8) However, since pancreatic cancers are known to be among the most aggressive malignancies despite their poor blood supply, we proposed that cancer cells' tolerance of insufficient nutrient might be an important determinant of malignancy. 9) Although the mechanism of tolerance has not yet been fully elucidated, the PI-3K-Akt pathway and AMPK have been found to be involved. 10) Because the blood supply of normal tissue is regulated in a sophisticated manner, angiogenesis is seldom activated in normal healthy adult tissues, except in the female reproductive system. 11) The same is true for nutrient starvation. We therefore speculated that if some compound could abolish cancer cells' tolerance of nutrient starvation, it might be capable of be...

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“…Tumor cells are continuously exposed to hypoxia and glucose starvation because the tumor's demand for their growth always exceeds the supply (Esumi et al 2002). In normal tissues, such as liver parenchyma, a relationship between binucleated cells and cell survival was reported (Morizur et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Binucleated HeLa cells are formed by cytokinesis failure in starvation and keep the potential of proliferation

et al. 2015

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Many cytological studies have reported that the numbers of binucleated cells were elevated in various tumors. However, binucleated cells are observed in not only malignant tumors but also normal tissues. Thus, the clinical significance of binucleated cells is controversial. Here we attempted to elucidate the characteristics of binucleated HeLa cells using time-lapse microscopy. To examine the frequency, viability, proliferation, and formation mechanism of binucleated cells, we grew HeLa cells on chamber slides and tissue culture dishes in DMEM supplemented with (10, 3, 1 and 0.5 % media) and without fetal bovine serum (0 % medium). The proliferation was evaluated by the medium improvement examination (cultured for 2 more days in 10% medium after culturing in 0% medium; starvation). In the 0 % medium, 150 binucleated cells were formed by cytokinesis failure. There were significantly more binucleated cells in the 0 % medium than in the 10, 3, 1 and 0.5 % media. About twice the number of binucleated cells underwent mitosis in the improvement examinations than in the serum-free examination. We found here that starvation induced the binucleation of HeLa cells and that some binucleated cells can reproduce. These findings might be helpful for understanding binucleated cells in tumors.

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Hypoxia and Nitric Oxide Treatment Confer Tolerance to Glucose Starvation in a 5′-AMP-activated Protein Kinase-dependent Manner

Cited by 78 publications

References 25 publications

Regulation of caspase-6 and FLIP by the AMPK family member ARK5

Regulation of caspase-6 and FLIP by the AMPK family member ARK5

Kigamicin D, a novel anticancer agent based on a new anti‐austerity strategy targeting cancer cells' tolerance to nutrient starvation

Binucleated HeLa cells are formed by cytokinesis failure in starvation and keep the potential of proliferation

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