Regulation of TRAIL Expression by the Phosphatidylinositol 3-Kinase/Akt/GSK-3 Pathway in Human Colon Cancer Cells

Wang, Qingding; Wang, Xiaofu; Hernandez, Ambrosio; Hellmich, Mark R.; Gatalica, Zoran; Evers, B. Mark

doi:10.1074/jbc.m206306200

Cited by 104 publications

(76 citation statements)

References 62 publications

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“…Finally, the PI3K-AKT pathway that operates at many levels of cell survival is involved in the positive regulation of NF-κB, COX-2 [54] and negative regulation of TRAIL [68] and TRAIL-R surface expression in melanomas, as we observed in the present study. On the other hand, treatment of melanoma cells with TRAIL in combination with the inhibitor of the PI3K-AKT pathway LY204002 substantially increased levels of cell death, especially necrotic death.…”

Section: Discussionsupporting

confidence: 80%

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Ivanov

Hei

2006

Experimental Cell Research

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AP-1/cJun, NF-κB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-κB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio-and chemotherapy. In the present study we observed strong effects of sodium arsenite treatment on upregulation of TRAILmediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-κB by sodium arsenite resulted in upregulation of the endogenous TRAIL-and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via down-regulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anti-cancer treatment.

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Section: Discussionsupporting

confidence: 80%

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Ivanov

Hei

2006

Experimental Cell Research

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“…RiboQuant MultiProbe RNase Protection Assay (RPA) System was used for the detection of multiple, specific mRNA species as we have previously described (38). 32 P-labeled antisense RNA probes were prepared using the Human Apoptosis hAPO-5 Template Set and hybridization performed according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Wang

Evers

2003

Journal of Biological Chemistry

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Activation of protein kinase C (PKC) prevents apoptosis in certain cells; however, the mechanisms are largely unknown. Inhibitors of apoptosis (IAP) family members, including NAIP, cIAP-1, cIAP-2, XIAP/hILP, survivin, and BRUCE, block apoptosis by binding and potently inhibiting caspases. Activation of NF-B contributes to cIAP-2 induction; however, the cellular mechanisms regulating cIAP-2 expression have not been entirely defined. In this study, we examined the role of the PKC and NF-B pathways in the regulation of cIAP-2 in human colon cancers. We found that cIAP-2 mRNA levels were markedly increased in human colon cancer cells by treatment with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or bryostatin 1. Inhibitors of the Ca 2؉ -independent, novel PKC isoforms, but not inhibitors of MAPK, PI3-kinase, or PKA, blocked PMA-stimulated cIAP-2 mRNA expression, suggesting a role of PKC in PMA-mediated cIAP-2 induction. Pretreatment with the PKC␦-selective inhibitor rottlerin or transfection with an antisense PKC␦ oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC␦ plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC␦ in cIAP-2 induction. Treatment with the proteasome inhibitor, MG132 or inhibitors of NF-B (e.g. PDTC and gliotoxin), decreased PMA-induced up-regulation of cIAP-2. PMAinduced NF-B activation was blocked by either GF109203x, MG132, PDTC, or gliotoxin. Moreover, overexpression of PKC␦-induced cIAP-2 promoter activity and increased NF-B transactivation, suggesting regulation of cIAP-2 expression by a PKC␦/NF-B pathway. In conclusion, our findings demonstrate a role for a PKC/NF-B-dependent pathway in the regulation of cIAP-2 expression in human colon cancer cells. These data suggest a novel mechanism for the anti-apoptotic function mediated by the PKC␦/NF-B/cIAP-2 pathway in certain cancers.

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“…Examples of these agents are retinoic acid, 146,147 interferons, 147,148 and PI3 kinase inhibitors. 149 Therefore, it is plausible to speculate that the combination of a death receptor-inducing drug with a death ligand-inducing agent may enhance the killing or elimination of malignant cancer cells via death ligand/death receptor-mediated apoptosis. Studying the effect of this kind of combination may develop an effective combination regimen for cancer therapy.…”

Section: Implications Of Death Receptor Modulation In Cancer Therapymentioning

confidence: 99%

Modulation of death receptors by cancer therapeutic agents

Elrod

Sun²

2008

Cancer Biology & Therapy

108

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Regulation of TRAIL Expression by the Phosphatidylinositol 3-Kinase/Akt/GSK-3 Pathway in Human Colon Cancer Cells

Cited by 104 publications

References 62 publications

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Modulation of death receptors by cancer therapeutic agents

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