Vascular Endothelial Growth Factor Transcriptional Activation Is Mediated by Hypoxia-inducible Factor 1α, HDM2, and p70S6K1 in Response to Phosphatidylinositol 3-Kinase/AKT Signaling

Abstract

Vascular endothelial growth factor (VEGF) expression is elevated in ovarian and other cancer cells. However, the mechanism that causes the increase in VEGF expression still remains to be elucidated. In this study, we demonstrated that activation of PI3K signaling mediated VEGF protein expression at the transcriptional level through hypoxia-inducible factor 1␣ (HIF-1␣) expression in human ovarian cancer cells. We found that inhibition of PI3K activity by LY294002 decreased VEGF transcriptional activation and that forced expression of AKT completely reversed the inhibitory effect. HDM2 and p70S6K1 are two downstream targets of AKT that mediate growth factor-induced VEGF transcriptional activation and HIF-1␣ expression. The inhibition of PI3K by LY294002 inhibited p70S6K1 and HDM2 activity in the cells. Forced expression of p70S6K1 or HDM2 reversed LY294002-inhibited VEGF transcriptional activation and HIF-1␣ expression. This study identifies a potential novel mechanism responsible for increased VEGF expression in ovarian cancer cells. It also indicates the important role of VEGF and HIF-1 in ovarian tumorigenesis and angiogenesis, which is mediated by the PI3K/AKT/HDM2 and AKT/p70S6K1 pathways in ovarian cancer cells.

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

“…However, little was known about the mechanism of FSH stimulation on VEGF expression. Other studies showed HIF-1α and survivin may play a role in VEGF expression [7][8][9][10][13][14][15][16], and it had also been shown that FSH induces HIF-1α and survivin expression [37][38][39]. In this study, we showed that treatment with FSH also increased survivin and HIF-1α expression (Figure 2A and 2B).…”

mTOR, translation initiation and cancer

“…S6K1 stimulates angiogenesis by increasing vascular endothelial growth factor (VEGF) production. Consistent with this, S6K1 overexpression reversed the LY294002-mediated inhibition of VEGF expression (Skinner et al, 2004). VEGF is essential for both physiological and pathological angiogenesis in cancer, such as ovarian cancers (Paley et al, 1997;Wang et al, 2006).…”

“…VEGF is essential for both physiological and pathological angiogenesis in cancer, such as ovarian cancers (Paley et al, 1997;Wang et al, 2006). Activation of PI3K signaling mediates VEGF expression through the hypoxia-inducible factor 1a (HIF-1a) in human ovarian cancer cells (Skinner et al, 2004). Taken together, these data suggest an important role for S6K1 in coordinating key processes associated with tumor invasiveness and angiogenesis in ovarian cancer.…”

“…A role for the S6 kinases in controlling the cell size has been suggested as their deletion results in smaller animals (Pende et al, 2004). Recent studies have addressed the specific role of S6K1 in tumor invasiveness, motility and angiogenesis (Skinner et al, 2004;Zhou and Wong, 2006). Zhou and Wong (2006) demonstrated a role for S6K1 in the motility and invasiveness phenotype activated by hepatocyte growth factor (HGF).…”

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

“…Furthermore, Akt promotes cell growth by phosphorylation of the downstream mTOR complex 1 (mTORC1) [45] , which translates mRNAs to protein via the p70S6K-S6 and 4E-BP1-eIF4E pathways [46] . In addition, hypoxia-inducible factor 1α (HIF-1α) was reported to be upregulated downstream of mTORC1, and therefore promotes angiogenesis by transcribing VEGF (vascular endothelial growth factor) [47] . However, phosphorylation of S6K negatively regulates insulin receptor substrate (IRS) and PI3K, leading to a feedback loop [48][49][50] .…”