PAK1 promotes colorectal cancer progression—new insights
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PAK1 promotes colorectal cancer progression—new insights

19/02/2026 Compuscript Ltd
P21-activated kinase 1 (PAK1), a serine/threonine kinase overexpressed in various malignancies, plays a central role in cytoskeletal remodeling, cell motility, and survival; however, the specific molecular mechanisms by which it maintains the stability of cancer-driving transcripts in CRC have remained elusive. In a recent study published in Genes & Diseases, researchers from the Jiangsu Institute of Cancer Research and the Affiliated Cancer Hospital of Nanjing Medical University identified a novel oncogenic mechanism of PAK1 and its significance in the growth and metastasis of CRC.

Using CRISPR/Cas9-mediated PAK1 knockout (KO) and lentiviral-mediated PAK1 overexpression (OE) cell lines, the authors demonstrated that targeting PAK1 effectively inhibits proliferation, migration, and invasion in vitro. GSEA results revealed significant enrichment in PI3K/AKT/mTOR signaling-related pathways, while further experimental validation indicated that PAK1 promotes CRC progression via the mTOR-S6K pathway.

Additionally, using data-independent acquisition (DIA) proteomic analysis, the authors observed a significant downregulation in the expression of PRSS3, CD44, PROS1, and SAA1 proteins in the PAK1 KO group. The concurrent inhibition of CD44 and SAA1 mRNAs suggested that PAK1 promotes CRC progression by preventing mRNA decay. Actinomycin D experiments confirmed the critical role of PAK1 in mediating the mRNA stability of these oncogenic genes.

To investigate whether PAK1 inhibition reverses chemoresistance, the authors used PF3758309 (PF-309), a small-molecule ATP-competitive inhibitor, to block PAK1 activity. They demonstrated that pharmacological blockade of the PAK1 kinase domain triggers rapid mRNA decay and suppresses multiple oncogenic signaling pathways. Furthermore, PAK1 inhibition exhibits a potent synergistic effect with oxaliplatin, significantly enhancing chemotherapeutic efficacy and inducing tumor regression in patient-derived organoids and in vivo models by accelerating mRNA degradation and halting protein synthesis.

In conclusion, this study establishes that PAK1 drives CRC progression by stabilizing the mRNA of oncogenic factors—specifically PRSS3, CD44, PROS1, and SAA1. Its genetic and pharmacological inhibition promotes the degradation of these transcripts, establishing PAK1 as a high-value therapeutic target for sensitizing colorectal tumors to standard-of-care treatments and overcoming chemoresistance.

Reference

Title of the original paper: Targeting PAK1 suppresses tumor progression by promoting mRNA decay of oncogenic factors and enhancing chemotherapeutic efficacy in colorectal cancer

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101683

Funding Information:
  • National Natural Science Foundation of China (Nos. 81902489 and 82172872)
  • Yishan Research Project of Jiangsu Cancer Hospital (No. YSZD/PY202408)
  • Key Research and Development Program of Jiangsu Province (BE2021745)
  • Natural Science Foundation of Jiangsu Province (BK20191079)
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4
Impact Factor: 9.4

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All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
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Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R

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https://tinyurl.com/48djkca4
Fichiers joints
  • PAK1 deficiency inhibits CRC progression. A) Relative mRNA expression levels of PAK1 in CRC cell lines (CACO2, DLD1, HT29, LoVo, SW480, and HCT116) compared with normal intestinal epithelial cells (HCoEpiC and NCM460). (B) Western blotting analysis of PAK1 protein levels in CRC cell lines and normal intestinal epithelial cells (HCoEpiC and NCM460). (C) Immunohistochemical staining of PAK1 in CRC tissues from the Human Protein Atlas (HPA) database. (D) Proliferation assays of DLD1 and HT29 cells with PAK1 knockout (KO) compared with wild-type (WT) cells. Cell viability was measured using the CCK8 assay at different time points (0, 24, 48, and 72 h). (E) Colony formation assays of DLD1 and HT29 cells with PAK1 KO compared with WT cells. (F) Migration and invasion assays of DLD1 and HT29 cells with PAK1 KO compared with WT cells. The data were presented as mean ± standard deviation, with statistical significance indicated (ns, no significance; ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001).
  • Synergistic effects of PF3758309 (PF-309) and oxaliplatin (OXA) in HCT116 cells. (A) Synergy analysis of PF-309 and OXA combination using SynergyFinder software in HCT116 cells. The HSA synergy score of 7.069 indicates a moderate level of synergy. (B) Determination of optimal concentrations for OXA (3125 nM) and PF-309 (1.53 nM) based on SynergyFinder analysis. (C) CCK-8 proliferation assay results show the cell viability of HCT116 cells treated with optimal concentrations of OXA, PF-309, and their combination over three days, measured by absorbance at 450 nm. The combination treatment significantly reduced cell proliferation. (D) Colony formation assay demonstrated that the combination treatment significantly decreased the number of colonies formed in HCT116 cells. (E) Transwell assay results indicate that the combination of PF-309 and OXA could significantly inhibit the migration and invasion of HCT116 cells. (F) Effect of PF-309 and OXA combination on CRC organoids. Treatment with PF-309, OXA, or their combination was applied to two CRC organoid models (P01 and P02). The combination treatment significantly reduced organoid size and viability, as indicated by ATP levels, compared with each drug alone. The scale bar represents 100 μm. The data were presented as mean ± standard deviation, with statistical significance indicated (ns, no significance; ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001).
  • The combination of PF3758309 (PF-309) plus oxaliplatin (OXA) enhances the inhibition of tumor growth in vivo. (A) The scheme of medication on tumor-bearing mice. (B) Images of tumor-bearing mice from each treatment group at the end of the experiment. (C) Images of the tumors dissected from the animals.(D) Body weight of mice during the treatment period. (E) Tumor weight of each group. (F) Tumor volume measurements over time in different groups. (G) Western blotting analysis of mTOR, CD44, and SAA1 protein levels in tumor tissues from different treatment groups. (H–J) Quantitative real-time PCR analysis of MTOR (H), CD44 (I), and SAA1 (J) mRNA expression levels in tumor tissues from different treatment groups. The data were presented as mean ± standard deviation, with statistical significance indicated (ns, no significance; ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001).
19/02/2026 Compuscript Ltd
Regions: Europe, Ireland, Asia, China
Keywords: Science, Life Sciences

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