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

Larsson, Per ; Syed Khaja, Azharuddin Sajid LU ; Semenas, Julius LU ; Wang, Tianyan ; Sarwar, Martuza LU ; Dizeyi, Nishtman LU ; Simoulis, Athanasios LU orcid ; Hedblom, Andreas LU ; Wai, Sun Nyunt and Ødum, Niels , et al. (2020) In International Journal of Cancer 146(6). p.1686-1699
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AKT, androgen receptor, matrix metalloproteinases 9, metastatic prostate cancer, PIP5K1α, targeted therapy
in
International Journal of Cancer
volume
146
issue
6
pages
14 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85071148602
  • pmid:31381135
ISSN
0020-7136
DOI
10.1002/ijc.32607
language
English
LU publication?
yes
id
fb8192b5-76de-4f67-816e-03f0c627e52e
date added to LUP
2019-09-03 09:10:35
date last changed
2025-01-09 21:13:30
@article{fb8192b5-76de-4f67-816e-03f0c627e52e,
  abstract     = {{<p>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.</p>}},
  author       = {{Larsson, Per and Syed Khaja, Azharuddin Sajid and Semenas, Julius and Wang, Tianyan and Sarwar, Martuza and Dizeyi, Nishtman and Simoulis, Athanasios and Hedblom, Andreas and Wai, Sun Nyunt and Ødum, Niels and Persson, Jenny L.}},
  issn         = {{0020-7136}},
  keywords     = {{AKT; androgen receptor; matrix metalloproteinases 9; metastatic prostate cancer; PIP5K1α; targeted therapy}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{6}},
  pages        = {{1686--1699}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer}},
  url          = {{http://dx.doi.org/10.1002/ijc.32607}},
  doi          = {{10.1002/ijc.32607}},
  volume       = {{146}},
  year         = {{2020}},
}