PAK4-targeting PROTAC inhibits bladder cancer cell proliferation
- 1Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
- 2Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
Abstract
p21-Activated kinase 4 (PAK4) is widely dysregulated and acts as an oncogene in multiple cancers, and the inhibition or knockout of PAK4 has shown excellent therapeutic effects in inhibiting tumor progression in combination with immunotherapy across a variety of cancers. Previously, we reported our self-developed peptide proteolysis-targeting chimera (PROTAC) drug PpD, which specifically and selectively degrades the PAK4 protein to effectively inhibit the growth of renal cancer tumors. In this study, we confirmed that the PAK4 protein is highly expressed in bladder cancer (BLCA) tissues. Moreover, we established PAK4 knockout BLCA cell lines and explored the regulatory mechanisms of PAK4 in BLCA via RNA sequencing. Our RNA sequencing results revealed that PAK4 promotes the cell cycle progression of BLCA cells and inhibits apoptosis. Comparative studies of the PAK4 knockout cell lines T-24 sg/PAK4 and 5637 sg/PAK4 with PpD drug treatment revealed that both PAK4 knockout and PpD drug treatment inhibited the ERK1/2/CDK4 pathway, thereby blocking the cell cycle transition from the G1 phase to the S phase, and both induced caspase-3-mediated apoptotic cell death. In vivo animal experiments also confirmed that the growth of BLCA cells was significantly inhibited in both the PAK4 knockout group and the PpD drug-treated group. Collectively, our findings indicate that PpD exhibits potent anti-tumor activity against BLCA and holds promising potential for therapeutic application in other cancers.
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BibTeX
@article{xu2026pak4targeting,
title = {{PAK4-targeting PROTAC inhibits bladder cancer cell proliferation}},
author = {Shan Xu and Hongjun Xie and Zhao Yang and Zhenkun Ma and Xiaojing Bai and Xiaoyu Feng and Jiale An and Bohan Ma},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0358561},
url = {https://doi.org/10.1371/journal.pone.0358561},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PAK4-targeting PROTAC inhibits bladder cancer cell proliferation
AU - Shan Xu
AU - Hongjun Xie
AU - Zhao Yang
AU - Zhenkun Ma
AU - Xiaojing Bai
AU - Xiaoyu Feng
AU - Jiale An
AU - Bohan Ma
PY - 2026
DA - 2026/09/21
JO - PLOS One
DO - 10.1371/journal.pone.0358561
UR - https://doi.org/10.1371/journal.pone.0358561
AB - p21-Activated kinase 4 (PAK4) is widely dysregulated and acts as an oncogene in multiple cancers, and the inhibition or knockout of PAK4 has shown excellent therapeutic effects in inhibiting tumor progression in combination with immunotherapy across a variety of cancers. Previously, we reported our self-developed peptide proteolysis-targeting chimera (PROTAC) drug PpD, which specifically and selectively degrades the PAK4 protein to effectively inhibit the growth of renal cancer tumors. In this study, we confirmed that the PAK4 protein is highly expressed in bladder cancer (BLCA) tissues. Moreover, we established PAK4 knockout BLCA cell lines and explored the regulatory mechanisms of PAK4 in BLCA via RNA sequencing. Our RNA sequencing results revealed that PAK4 promotes the cell cycle progression of BLCA cells and inhibits apoptosis. Comparative studies of the PAK4 knockout cell lines T-24 sg/PAK4 and 5637 sg/PAK4 with PpD drug treatment revealed that both PAK4 knockout and PpD drug treatment inhibited the ERK1/2/CDK4 pathway, thereby blocking the cell cycle transition from the G1 phase to the S phase, and both induced caspase-3-mediated apoptotic cell death. In vivo animal experiments also confirmed that the growth of BLCA cells was significantly inhibited in both the PAK4 knockout group and the PpD drug-treated group. Collectively, our findings indicate that PpD exhibits potent anti-tumor activity against BLCA and holds promising potential for therapeutic application in other cancers.
SN - 1932-6203
ER -