Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Trisciuoglio, Daniela; Iervolino, Angela; Zupi, Gabriella; Bufalo, Donatella Del

doi:10.1091/mbc.e04-12-1087

Cited by 81 publications

(67 citation statements)

References 42 publications

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“…In 4T1 cells, ras-induced VEGF secretion was partly inhibited by either a MEK inhibitor or a PI3K inhibitor, but was markedly inhibited by both when given together, i.e., we could see the synergistic effect of both pathways in the expression of VEGF in tumor cells. Such synergism from the use of PI3K and MAPK inhibitors has been reported when angiogenic factors were induced in myeloma, melanoma, and gastric cancer cells (42)(43)(44).…”

Section: Regulation Of Vegf Expression By Mapk and Pi3k In Tumor Cellsmentioning

confidence: 55%

Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells

Venkatesha

Hanai

Seth

et al. 2006

Molecular Cancer Research

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Lipocalin 2 is an iron-binding secreted protein that converts embryonic kidney mesenchyme to epithelia. Previously, we reported that lipocalin 2 could revert 4T1-ras-transformed mesenchymal tumor cells to a more epithelial phenotype, increase E-cadherin expression, and suppress cell invasiveness in vitro and in vivo, indicating that lipocalin 2 is a metastasis suppressor. Here, we show that lipocalin 2 can suppress the ras-induced expression of vascular endothelial growth factor in 4T1 cells via down-regulation of ras mitogenactivated protein kinase and ras phosphatidylinositol-3-kinase signaling. In addition, the expression of thrombospondin-1 (an antiangiogenic molecule) was increased in tumors formed by 4T1-ras cells into which lipocalin 2 was stably introduced. Tumor angiogenesis, assessed via an intradermal tumor angiogenesis assay, was also suppressed by lipocalin 2. We also show that caveolin-1 is a critical mediator of this activity. These data provide new insights into the action of lipocalin 2 and raise the possibility that the administration of lipocalin 2 may be useful for inhibiting tumor angiogenesis, in addition to suppressing tumor metastasis, in cancers which show ras activation. (Mol Cancer Res 2006;4(11):821 -9)

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Section: Regulation Of Vegf Expression By Mapk and Pi3k In Tumor Cellsmentioning

confidence: 55%

Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells

Venkatesha

Hanai

Seth

et al. 2006

Molecular Cancer Research

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“…This suggests that NF-kB transcriptional activity is decreased upon downregulation of IL-8 signaling in hypoxic cells and provides a mechanism that may explain the increased sensitivity of hypoxic prostate cancer cells to etoposide when IL-8 signaling is impaired. Other studies from our laboratory have confirmed that IL-8 signaling potentiates NF-kB-mediated transcription of antiapoptotic genes (Wilson et al, in preparation) and activates the phosphoinositide-3 kinase (PI3K)/Akt and mitogenactivated protein kinase (MAPK) signaling cascades in PC3 cells (MacManus et al, 2007), pathways that are central to cell survival (Takami et al, 2002;Heidemann et al, 2003) and whose activity is increased in hypoxic cells (Trisciuoglio et al, 2005). Therefore, we suggest that IL-8 signaling may enable the survival of hypoxic prostate cancer cells and that strategies to inhibit IL-8 signaling may be a therapeutic option to sensitize hypoxic prostate cancer cells to conventional chemotherapy.…”

Section: Discussionmentioning

confidence: 78%

HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells

et al. 2007

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Hypoxic cancer cells are resistant to treatment, leading to the selection of cells with a more malignant phenotype. The expression of interleukin-8 (IL-8) plays an important role in the tumorigenesis and metastasis of solid tumors including prostate cancer. Recently, we detected elevated expression of IL-8 and IL-8 receptors in human prostate cancer tissue. The objective of the current study was to determine whether hypoxia increases IL-8 and IL-8 receptor expression in prostate cancer cells and whether this contributes to a survival advantage in hypoxic cells. IL-8, CXCR1 and CXCR2 messenger RNA (mRNA) expression in PC3 cells was upregulated in response to hypoxia in a time-dependent manner. Elevated IL-8 secretion following hypoxia was detected by enzymelinked immunosorbent assay, while immunoblotting confirmed elevated receptor expression. Attenuation of hypoxia-inducible factor (HIF-1) and nuclear factor-jB (NF-jB) transcriptional activity using small interfering RNA (siRNA), a HIF-1 dominant-negative and pharmacological inhibitors, abrogated hypoxia-induced transcription of CXCR1 and CXCR2 in PC3 cells. Furthermore, chromatin-IP analysis demonstrated binding of HIF-1 and NF-jB to CXCR1. Finally, inhibition of IL-8 signaling potentiated etoposide-induced cell death in hypoxic PC3 cells. These results suggest that IL-8 signaling confers a survival advantage to hypoxic prostate cancer cells, and therefore, strategies to inhibit IL-8 signaling may sensitize hypoxic tumor cells to conventional treatments.

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“…While tumor cells express VEGF necessary for the chemotaxis of endothelial cells into the growing tumor tissue, the process of wound angiogenesis is dependent on endogenously expressed VEGF produced by various cells, including macrophages and keratinocytes [13,27]. Thus, inactivation of Akt causes inhibition of VEGF expression as has been reported by several groups [29,33,38,41]. In turn, reduced VEGF levels seem to be responsible for defective angiogenesis in wounds of Akt1 -/-mice.…”

Section: Discussionmentioning

confidence: 81%

Akt1 is necessary for the vascular maturation and angiogenesis during cutaneous wound healing

2008

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Previous in vivo and in vitro studies have shown that Akt1 serves as a crucial regulator of vascular maturation, extracellular matrix composition, and angiogenesis in tumors. Hence, we hypothesized that Akt1 may be necessary for other angiogenesis-dependent processes, including wound healing. Using Akt1 -/-and Akt2 -/-mice, we demonstrate that deficiency of Akt1, but not Akt2, results in impaired assembly of collagen in skin wounds and around the blood vessels. Wounds in Akt1 -/-mice, but not in Akt2 -/-mice, were characterized by reduced vascular area as well as impaired vascular maturation as evidenced by reduced smooth muscle cell recruitment. Expression level of a major angiogenic growth factor, VEGF, was significantly lower in wound tissues of Akt1 -/-mice as compared to WT. However, despite the impaired collagen assembly and reduced angiogenesis in Akt1 -/-wounds, no significant difference in migration of fibroblasts into the wound area was observed between WT and Akt1 -/-mice. Importantly, the dynamics of wound closure were similar between WT, Akt1 -/-, and Akt2 -/-mice. Thus, it appears that although the lack of Akt1 impairs VEGF expression, wound angiogenesis, and subsequent maturation of vasculature, it has no effect on the wound closure. These findings may have clinical applications for the improvement of treatment procedures with reported history of wound healing complications.

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Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Cited by 81 publications

References 42 publications

Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells

Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells

HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells

Akt1 is necessary for the vascular maturation and angiogenesis during cutaneous wound healing

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