Intracrine VEGF Signaling Mediates the Activity of Prosurvival Pathways in Human Colorectal Cancer Cells

Abstract

The effects of vascular endothelial growth factor-A (VEGF-A/VEGF) and its receptors on endothelial cells function has been studied extensively, but their effects on tumor cells are less well defined. Studies of human colorectal cancer (CRC) cells where the VEGF gene has been deleted suggest an intracellular role of VEGF as a cell survival factor. In this study, we investigated the role intracrine VEGF signaling in CRC cell survival. In human CRC cells, RNAi-mediated depletion of VEGF decreased cell survival and enhanced sensitivity to chemotherapy. Unbiased reverse phase protein array studies and subsequent validation experiments indicated that impaired cell survival was a consequence of disrupted AKT and ERK1/2 (MAPK3/1) signaling, as evidenced by reduced phosphorylation. Inhibition of paracrine or autocrine VEGF signaling had no effect on phospho-AKT or phospho-ERK1/2 levels, indicating that VEGF mediates cell survival via an intracellular mechanism. Notably, RNAi-mediated depletion of VEGF receptor VEGFR1/FLT1 replicated the effects of VEGF depletion on phospho-AKT and phospho-ERK1/2 levels. Together, these studies show how VEGF functions as an intracrine survival factor in CRC cells, demonstrating its distinct role in CRC cell survival.

Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells

“…In colorectal cancer cells, VEGFA depletion reduces cell survival and enhances chemosensitivity via blockade of AKT and ERK1/2 pathways57. An autocrine VEGFA/VEGFR2 pathway opposes apoptosis in leukaemia cells through induction of the anti-apoptotic protein Bcl-258.…”

Effects of vascular endothelial growth factors and their receptors on megakaryocytes and platelets and related diseases

“…It was recently reported the VEGFA‐VEGFR1 axis acted as an intracrine mode via the apoptosis [caspase‐3, cleaved PARP, BAX and survivin (BIRC5)] (Samuel et al , ), survival (AKT) (Bhattacharya et al , ), and proliferation (ERK1/2) (Bhattacharya et al , ) pathways to promote the survival of colorectal cancer cells. MKs and platelets noticeably possess a fully functional intrinsic apoptosis pathway (Kile, ).…”

“…More recently, the data from our laboratory indicated that the level of VEGFR2 was significantly enhanced in the SP600125‐induced polyploidy model of megakaryocytic cell lines (unpublished data). VEGFA depletion noticeably impaired the phosphorylation of S6K1 (RPS6KB1) and PRAS40 (AKT1S1), which are downstream of the AKT pathway (Bhattacharya et al , ). Given that VEGFs and VEGFRs are expressed in normal primary MKs and megakaryocytic cell lines as well as in MKs from related haematological disorders and they are involved in survival, proliferation, differentiation and polyploidization, we reasonably proposed that intracrine VEGF/VEGFR signalling may be implicated in the development of MKs and the pathology of the abnormal megakaryocytopoiesis‐related diseases via a similar manner as in solid tumours, and thus might be used as therapeutic targets (Hasselbalch, ) (Fig ).…”

Vascular endothelial growth factor A/Vascular endothelial growth factor receptor 2 axis promotes human dental pulp stem cell migration via the FAK/PI3K/Akt and p38 MAPK signalling pathways

“…As a chemokine and mitogen, VEGF binds with its prime receptor VEGFR2 to play a key role in endothelial cell survival and angiogenesis (Karali et al 2014). On the other hand, VEGFR1 participates in migration, invasion and survival of human colorectal cancer cells via a novel intracrine mechanism that is diverse from the canonical autocrine or paracrine roles of VEGF (Bhattacharya et al 2016(Bhattacharya et al , 2017. On the other hand, VEGFR1 participates in migration, invasion and survival of human colorectal cancer cells via a novel intracrine mechanism that is diverse from the canonical autocrine or paracrine roles of VEGF (Bhattacharya et al 2016(Bhattacharya et al , 2017.…”

“…The binding of VEGF to VEGFR2 brings receptor autophosphorylation and initiates a string of signalling cascades, resulting in cell proliferation, migration and survival (Simons et al 2016). On the other hand, VEGFR1 participates in migration, invasion and survival of human colorectal cancer cells via a novel intracrine mechanism that is diverse from the canonical autocrine or paracrine roles of VEGF (Bhattacharya et al 2016(Bhattacharya et al , 2017. Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) are activated by VEGF in endothelial cells to enhance cell migration (Chiu et al 2013).…”