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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Ma, Yi Dumesny, Chelsea Dong, Li Ang, Ching-Seng Asadi, Khashayar Zhan, Yifan Nikfarjam, Mehrdad He, Hong |
| Abstract | Background Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer, and KRAS oncogene occurs in over 90% of cases. P21-activated kinases (PAK), containing six members (PAK1 to 6), function downstream of KRAS. PAK1 and PAK4 play important roles in carcinogenesis, but their combinational effect remains unknown. In this study, we have determined the effect of dual inhibition of PAK1 and PAK4 in PDA progression using knockout (KO) cancer cell lines. Methods Murine wild-type (WT) and PAK1KO pancreatic cancer cell lines were isolated from PAK1+/+ and PAK1−/− KPC (LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx-1-Cre) mice. KPC PAK4KO and KPC PAK1&4 KO cell lines were generated from KPC WT and KPC PAK1KO cell lines respectively using the CRISPR-CAS9 gene knockout technique. PAK WT and KO cell lines were used in mouse models of pancreatic tumours. Cells and tumour tissue were also used in flow cytometry and proteomic studies. A human PDA tissue microarray was stained by immunohistochemistry. Results Double knock out of PAK1 and PAK4 caused complete regression of tumour in a syngeneic mouse model. PAK4KO inhibited tumour growth by stimulating a rapid increase of cytotoxic CD8+ T cell infiltration. PAK1KO synergistically with PAK4KO increased cytotoxic CD8+ T cell infiltration and stimulated a sustained infiltration of CD8+ T cells at a later phase to overcome the immune evasion in the PAK4KO tumour. The human PDA tissue microarray study showed the important role of PAK1 and PAK4 in intra-tumoral T-cell function. Conclusion Our results demonstrated that dual inhibition of PAK1 and PAK4 synergistically suppressed PDA progression by stimulating cytotoxic CD8 + T cell response. |
| Related Links | https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-024-01670-2.pdf |
| Ending Page | 15 |
| Page Count | 15 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| DOI | 10.1186/s12964-024-01670-2 |
| Journal | Cell Communication and Signaling |
| Issue Number | 1 |
| Volume Number | 22 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2024-05-27 |
| Access Restriction | Open |
| Subject Keyword | Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors P21-activated kinases1&4 Intra-tumoral T cells Pancreatic ductal adenocarcinoma |
| Content Type | Text |
| Resource Type | Article |
| Subject | Biochemistry Cell Biology Molecular Biology |
| Journal Impact Factor | 8.2/2023 |
| 5-Year Journal Impact Factor | 8/2023 |
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