The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer. / Larsson, Per; Syed Khaja, Azharuddin Sajid; Semenas, Julius; Wang, Tianyan; Sarwar, Martuza; Dizeyi, Nishtman; Simoulis, Athanasios; Hedblom, Andreas; Wai, Sun Nyunt; Ødum, Niels; Persson, Jenny L.
In: International Journal of Cancer, Vol. 146, No. 6, 2020, p. 1686-1699.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer
AU - Larsson, Per
AU - Syed Khaja, Azharuddin Sajid
AU - Semenas, Julius
AU - Wang, Tianyan
AU - Sarwar, Martuza
AU - Dizeyi, Nishtman
AU - Simoulis, Athanasios
AU - Hedblom, Andreas
AU - Wai, Sun Nyunt
AU - Ødum, Niels
AU - Persson, Jenny L.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - AKT
KW - androgen receptor
KW - matrix metalloproteinases 9
KW - metastatic prostate cancer
KW - PIP5K1α
KW - targeted therapy
U2 - 10.1002/ijc.32607
DO - 10.1002/ijc.32607
M3 - Journal article
C2 - 31381135
AN - SCOPUS:85071148602
VL - 146
SP - 1686
EP - 1699
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 6
ER -
ID: 226876885