Regulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Angiogenesis by an Insulin-Like Growth Factor-I Receptor Autocrine Loop in Human Pancreatic Cancer

Stoeltzing, Oliver; Liu, Wenbiao; Reinmuth, Niels; Fan, Fan; Parikh, Alexander A.; Bucana, Corazon D.; Evans, Douglas B.; Semenza, Gregg L.; Ellis, Lee M.

doi:10.1016/s0002-9440(10)63460-8

Cited by 151 publications

(153 citation statements)

References 39 publications

(52 reference statements)

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“…We found that the p38 selective inhibitor SB203580 suppressed IGF-I-induced activation of COX-2 promoter activity and mRNA stabilization. This is consistent with previous findings showing that p38 MAPK was involved in COX-2 transcription presumably through increasing AP-1 activity (41,(45)(46)(47), and that p38 MAPK regulated COX-2 mRNA stabilization by its downstream kinase MK-2 (9,36,48).…”

Section: Discussionsupporting

confidence: 93%

“…In addition, IGF-IR is involved not only in the induction of cell transformation, but also in the maintenance of the transformed phenotype (5). Furthermore, IGF-I has been implicated in tumor neovascularization by increasing the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) (6)(7)(8)(9). Despite these findings, however, the molecular mechanisms by which IGF-I contributes to cancer progression remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

Cao

Liu

Dixon

et al. 2007

Cellular Signalling

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Elevated levels of insulin-like growth factor-I (IGF-I) are associated with ovarian carcinogenesis and progression. However, the molecular mechanisms by which IGF-I contributes to ovarian cancer development remain to be elucidated. Cyclooxygenase-2 (COX-2) is a crucial player in the pathogenesis of human malignancies. Herein we showed that IGF-I efficiently induced COX-2 expression and PGE 2 biosynthesis at physiologically relevant concentrations in human ovarian cancer cells. IGF-I treatment significantly increased COX-2 transcriptional activation. IGF-I also stabilized COX-2 mRNA through the COX-2 3′-untranslated region (3′-UTR), which appeared independent of the conserved AU-rich elements. We next investigated the signaling pathways involved in IGF-I-induced COX-2 expression. We found that PI3K inhibitor wortmannin or LY294002 blocked COX-2 expression induced by IGF-I. Wortmannin treatment or a dominant negative PI3K mutant significantly inhibited IGF-I-induced COX-2 mRNA stabilization, but only slightly decreased COX-2 transcriptional activation. We showed that ERK1/2 and p38 MAPKs were required for IGF-I-induced COX-2 expression and that activation of both pathways by IGF-I increased COX-2 transcriptional activation and its mRNA stability. IGF-I stimulated PKC activation in the cells and pretreatment with PKC inhibitor bisindolylmaleimide prevented IGF-I-induced COX-2 transcriptional activation and mRNA stabilization, and inhibited COX-2 mRNA and protein expression. Taken together, our data demonstrate that IGF-I induces COX-2 expression in human ovarian cancer cells, which is mediated by three parallel signaling cascades -PI3K, MAPK, and PKC pathways that differentially regulate COX-2 expression at transcriptional and posttranscriptional levels.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

Cao

Liu

Dixon

et al. 2007

Cellular Signalling

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“…In vitro studies have demonstrated that IGF-I and IGF-II are potent mitogens for cultured human pancreatic cancer cells (Ohmura et al, 1990;Bergmann et al, 1995;Stoeltzing et al, 2003;Zeng et al, 2003) and that IGF binding proteins can have opposing actions, in part by binding IGF-I and IGF-II (Rechler, 1997), but also by direct inhibitory effects on target cells (Rajah et al, 1997). The IGF axis also interacts with the insulin pathway, as elevated levels of insulin increase free, biologically active IGF-I, and alter concentrations of several IGF binding proteins (Giovannucci, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…lines, where initiation of intracellular signalling through IGF-IR leads to decreased apoptosis and increased proliferation, invasion, and expression of mediators of angiogenesis (Ohmura et al, 1990;Bergmann et al, 1995;Stoeltzing et al, 2003;Zeng et al, 2003;Neid et al, 2004).…”

mentioning

confidence: 99%

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts

et al. 2007

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Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case -control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60 -1.48), 0.96 (95% CI, 0.61 -1.52), and 1.21 (95% CI, 0.75 -1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54 -1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.

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“…In favor of this hypothesis are results from a recently published study demonstrating that KRAS activation promotes KLF5 up-regulation in human colon cancer (HCT116) cells (13). Moreover, because hypoxia-mediated and cytokine-mediated activation of the oncogenic transcription factor hypoxia-inducible factor-1α (HIF-1α) is frequently encountered in pancreatic tumors, we also hypothesized that the interleukin (IL)-1β system and/or HIF-1α may be involved in the regulation of KLF5 expression (14)(15)(16)(17)(18). We therefore sought to further define the expression and regulation of KLF5 in human pancreatic cancer cells to expand our knowledge on this particular transcription factor and to potentially reveal a novel molecular therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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Krüppel-like factor 5 (KLF5) is a transcription factor involved in cell transformation, proliferation, and carcinogenesis that can be up-regulated by RAS mutations. However, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Because KRAS is frequently mutated in pancreatic cancer, we investigated the regulation of KLF5 in this cancer entity. Our results show that KLF5 is overexpressed in pancreatic cancer cells and exceeds KLF5 expression of KRAS-mutated colon cancer cells. Surprisingly, inhibition of B-Raf/C-Raf or MAPK/Erk did not reduce KLF5 levels, suggesting that KLF5 expression is not promoted by KRAS-Raf-MEK-Erk signaling in pancreatic cancer. This finding is in striking contrast to reports on MEK-Erk-mediated KLF5 induction in colon cancer cells. Moreover, KLF5 expression levels neither correlated with the mutational status of KRAS nor with MEK phosphorylation in pancreatic cancer cells. Importantly, KLF5 was significantly up-regulated by interleukin (IL)-1β or hypoxia. The IL-1 β-mediated induction of KLF5 was diminished by blocking the p38 pathway. In addition, blocking IL-1R reduced the constitutive KLF5 expression, suggesting an autocrine activation loop. Moreover, KLF5 coimmunoprecipitated with hypoxia-inducible factor-1α (HIF-1α) and HIF-1α siRNA reduced constitutive KLF5. Similarly, KLF5 siRNA reduced the expression of the HIF-1α target gene GLUT-1. Furthermore, KLF5 expression was significantly elevated by high cell density, by anchorage-independent cell growth, and in tumor spheroids. Down-regulation of KLF5 by RNAi reduced the expression of the target genes, survivin, and platelet-derived growth factor-A. In conclusion, overexpression of KLF5 in human pancreatic cancer cells is not mediated by KRAS/Raf/ MAPK/Erk signaling, but involves the IL-1β/IL-1R system, p38, and the transcription factor

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Regulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Angiogenesis by an Insulin-Like Growth Factor-I Receptor Autocrine Loop in Human Pancreatic Cancer

Cited by 151 publications

References 39 publications

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

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