Cross Talk between Apoptosis and Invasion Signaling in Cancer Cells through Caspase-3 Activation

Mukai, Mutsuko; Kusama, Toshiyuki; Hamanaka, Yuri; Koga, Takumi; Endo, Hideki; Tatsuta, Masaharu; Inoue, Masahiro

doi:10.1158/0008-5472.can-04-4344

Cited by 36 publications

(20 citation statements)

References 16 publications

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“…Cancer Res 2007; 67: (17 In AsPC-1 cells, suppression of protein synthesis by cycloheximide also inhibited the cell death induced by IGF-I under anoxic conditions (Fig. 5C, left).…”

Section: Cancer Researchmentioning

confidence: 89%

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Activation of Insulin-like Growth Factor Signaling Induces Apoptotic Cell Death Under Prolonged Hypoxia by Enhancing Endoplasmic Reticulum Stress Response

et al. 2007

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Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Mammalian target of rapamycin (mTOR), one of the downstream molecules of the insulin-like growth factor (IGF) pathway, is a key regulator of translation, integrating multiple environmental and nutritional cues. The activity of mTOR is known to be suppressed under hypoxic conditions in cancer cells, whereas the contribution of this suppression to cell survival has not yet been clarified. We show that stimulating IGF signaling provoked caspase-dependent apoptosis under low oxygen tension in two cancer cell lines, COLO 320 and AsPC-1. In concurrence with increased levels of BAD phosphorylation, cell death was not accompanied by cytochrome c release from mitochondria. The cells were rescued from apoptosis when phosphatidylinositol 3-kinase (PI3K) or mTOR activity was inhibited, suggesting that these signals are critical in the observed cell death. IGFs and insulin enhanced the endoplasmic reticulum (ER) stress response as monitored by induction of the CCAAT/enhancer binding protein homologous protein (CHOP) proteins and the X box protein-1 splicing under hypoxic conditions, and this response was suppressed by inhibiting PI3K and mTOR activity. IGF-induced cell death under hypoxic conditions was prevented by treatment with cycloheximide, suggesting that de novo protein synthesis is required. Indeed, suppression of CHOP protein levels with small hairpin RNA reduced cell death. Taken together, the data suggest that stimulating IGF signaling under hypoxic conditions provokes apoptosis by enhancing the ER stress response. [Cancer Res 2007;67(17):8095-103]

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“…Cancer Res 2007; 67: (17 In AsPC-1 cells, suppression of protein synthesis by cycloheximide also inhibited the cell death induced by IGF-I under anoxic conditions (Fig. 5C, left).…”

Section: Cancer Researchmentioning

confidence: 89%

“…Gene silencing was done using the pSuperRetro plasmid purchased from Oligoengine as previously described (17). The corresponding sequence of the CHOP oligonucleotide was 5 ¶-gtcctgtcttcagatgaaa-3 ¶.…”

Section: Methodsmentioning

confidence: 99%

Activation of Insulin-like Growth Factor Signaling Induces Apoptotic Cell Death Under Prolonged Hypoxia by Enhancing Endoplasmic Reticulum Stress Response

et al. 2007

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“…Immunocytochemistry-Immunocytochemistry was performed as described previously (16). The details are described in the supplemental material.…”

Section: Methodsmentioning

confidence: 99%

Cellular Hypoxia of Pancreatic β-Cells Due to High Levels of Oxygen Consumption for Insulin Secretion in Vitro

Sato

Endo

Okuyama

et al. 2011

Journal of Biological Chemistry

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144

138

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Cellular oxygen consumption is a determinant of intracellular oxygen levels. Because of the high demand of mitochondrial respiration during insulin secretion, pancreatic ␤-cells consume large amounts of oxygen in a short time period. We examined the effect of insulin secretion on cellular oxygen tension in vitro. We confirmed that Western blotting of pimonidazole adduct was more sensitive than immunostaining for detection of cellular hypoxia in vitro and in vivo. The islets of the diabetic mice but not those of normal mice were hypoxic, especially when a high dose of glucose was loaded. In MIN6 cells, a pancreatic ␤-cell line, pimonidazole adduct formation and stabilization of hypoxia-inducible factor-1␣ (HIF-1␣) were detected under mildly hypoxic conditions. Inhibition of respiration rescued the cells from becoming hypoxic. Glucose stimulation decreased cellular oxygen levels in parallel with increased insulin secretion and mitochondrial respiration. The cellular hypoxia by glucose stimulation was also observed in the isolated islets from mice. The MIN6 cells overexpressing HIF-1␣ were resistant to becoming hypoxic after glucose stimulation. Thus, glucose-stimulated ␤-cells can become hypoxic by oxygen consumption, especially when the oxygen supply is impaired.

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“…We tested the effect of GRI977143 in an in vitro invasion model that has been considered a realistic model of metastasis (Mukai et al, 2000(Mukai et al, , 2005Uchiyama et al, 2007). Stimulation of MM1 hepatocarcinoma cells with GRI977143 elicited a dose-dependent increase in the number of cells that penetrated the HUVEC monolayer (Fig.…”

Section: Discussionmentioning

confidence: 99%

Virtual Screening for LPA₂-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions

et al. 2012

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Lysophosphatidic acid (LPA) is a highly potent endogenous lipid mediator that protects and rescues cells from programmed cell death. Earlier work identified the LPA 2 G proteincoupled receptor subtype as an important molecular target of LPA mediating antiapoptotic signaling. Here we describe the results of a virtual screen using single-reference similarity searching that yielded compounds 2-((9-oxo-9H-fluoren-2-yl) carbamoyl)benzoic acid (NSC12404), 2-((3-(1,3-dioxo-1H-benzo- [de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid (GRI977143), 4,5-dichloro-2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid (H2L55-47924), and 2-((9,10-dioxo-9,10-dihydroanthracen-2-yl)carbamoyl) benzoic acid (H2L5828102), novel nonlipid and drug-like compounds that are specific for the LPA 2 receptor subtype. We characterized the antiapoptotic action of one of these compounds, GRI977143, which was effective in reducing activation of caspases 3, 7, 8, and 9 and inhibited poly(ADP-ribose)polymerase 1 cleavage and DNA fragmentation in different extrinsic and intrinsic models of apoptosis in vitro.Furthermore, GRI977143 promoted carcinoma cell invasion of human umbilical vein endothelial cell monolayers and fibroblast proliferation. The antiapoptotic cellular signaling responses were present selectively in mouse embryonic fibroblast cells derived from LPA 1&2 double-knockout mice reconstituted with the LPA 2 receptor and were absent in vector-transduced control cells. GRI977143 was an effective stimulator of extracellular signal-regulated kinase 1/2 activation and promoted the assembly of a macromolecular signaling complex consisting of LPA 2 , Na ϩ -H ϩ exchange regulatory factor 2, and thyroid receptor interacting protein 6, which has been shown previously to be a required step in LPA-induced antiapoptotic signaling. The present findings indicate that nonlipid LPA 2 -specific agonists represent an excellent starting point for development of lead compounds with potential therapeutic utility for preventing the programmed cell death involved in many types of degenerative and inflammatory diseases.

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Cross Talk between Apoptosis and Invasion Signaling in Cancer Cells through Caspase-3 Activation

Cited by 36 publications

References 16 publications

Activation of Insulin-like Growth Factor Signaling Induces Apoptotic Cell Death Under Prolonged Hypoxia by Enhancing Endoplasmic Reticulum Stress Response

Activation of Insulin-like Growth Factor Signaling Induces Apoptotic Cell Death Under Prolonged Hypoxia by Enhancing Endoplasmic Reticulum Stress Response

Cellular Hypoxia of Pancreatic β-Cells Due to High Levels of Oxygen Consumption for Insulin Secretion in Vitro

Virtual Screening for LPA₂-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions

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Cross Talk between Apoptosis and Invasion Signaling in Cancer Cells through Caspase-3 Activation

Cited by 36 publications

References 16 publications

Activation of Insulin-like Growth Factor Signaling Induces Apoptotic Cell Death Under Prolonged Hypoxia by Enhancing Endoplasmic Reticulum Stress Response

Activation of Insulin-like Growth Factor Signaling Induces Apoptotic Cell Death Under Prolonged Hypoxia by Enhancing Endoplasmic Reticulum Stress Response

Cellular Hypoxia of Pancreatic β-Cells Due to High Levels of Oxygen Consumption for Insulin Secretion in Vitro

Virtual Screening for LPA2-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions

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Virtual Screening for LPA₂-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions