The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer

Abstract

Currently, no effective targeted therapeutics exists for treatment of metastatic prostate cancer (PCa). Given that matrix metalloproteinases 9 (MMP9) and its associated vascular endothelial growth factor (VEGF) are critical for tumor vascularization and invasion under castration‐resistant condition, it is therefore of great importance to define the functional association and interplay between androgen receptor (AR) and MMP9 and their associated key survival and invasion pathways in PCa cells. Here, we found that there was a significant correlation between MMP9 and AR protein expression in primary and metastatic PCa tissues, and a trend that high level of MMP9 expression was associated with poor prognosis. We demonstrated that constitutive activation of AR increased expression of MMP9 and VEGF/VEGF receptors. We further showed that AR exerts its effect on MMP9/VEGF signaling axis through PIP5K1α/AKT. We showed that MMP9 physically interacted with PIP5K1α via formation of protein–protein complexes. Furthermore, elevated expression of MMP9 enhanced ability of AR to activate its target gene cyclin A1. The elevated sequential activation of AR/PIP5K1α/AKT/MMP9/VEGF signaling axis contributed to increased invasiveness and growth of metastatic tumors. Conversely, treatment with PIP5K1α inhibitor significantly suppressed invasiveness of PCa cells expressing constitutively activated AR, this was coincident with its inhibitory effect of this inhibitor on AR/MMP9/VEGF pathways. Our results suggest that AR and MMP9‐associated network proteins may be effectively targeted by blocking PIP5K1α/AKT pathways using PIP5K1α inhibitor in metastatic PCa.

Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase

“…By contrast, ISA-2011B exhibited a significant inhibitory effect on the proliferation of PC-3 cells that had a high level of PIP5K1α ( Figure 6 f). These results are consistent with our recent reported studies showing that ISA-2011B treatment resulted in the reduced proliferation and invasiveness of PCa cells [ 25 ].…”

Effect of Sulfated Polysaccharide from Undaria pinnatifida (SPUP) on Proliferation, Migration, and Apoptosis of Human Prostatic Cancer

“…MMPs have been shown to be important targets for treating metastatic prostate cancer. For example, Larsson et al found that MMP9 can increase the aggressiveness of metastatic cancer and promote the growth of metastatic tumors by interacting with other factors [15]. Li et al found that reducing the expression of MMP-9 in prostate cancer cells was accompanied by a decrease in cell invasion and migration [16].…”

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

“…In prostate cancer, MMP-9 may amplify local angiogenesis by cleaving membranebound VEGF. Therefore, VEGF is a candidate to be blocked and controlled and to prevent the activation of the androgen receptor (AR)/phosphatidylinositol 4-phosphate 5-kinase type-1 alpha (PIP5K1α)/AKT/MMP-9/VEGF signaling axis required for cell survival and invasion of metastatic tumors (198). Similarly, the effect of phytochemicals on MMP-2, MMP-9, and their tissue inhibitors (TIMPs) has been tested in breast cancer, with no alterations observed in vitro (199).…”