Inhibiting p21-activated kinase (PAK7) enhances radiosensitivity in hepatocellular carcinoma

Abstract

Objective: In light of the upregulation of p21-activated kinase (PAK7) in a variety of cancers, including hepatocellular carcinoma (HCC), we aimed to investigate the effect of PAK7 on the sensitivity of HCC cells to radiotherapy. Methods: PAK7 expression was determined in normal adult liver epithelial THLE-2 and human HCC cell lines. The effect of ionizing radiation (IR) on the HCC cell viability was evaluated by Sulforhodamine B (SRB) assay. HCC cell lines Mahlavu and Huh7 were chosen to assess the effect of PAK7 shRNAs on the viability, clone formation, apoptosis, cycle distribution and γ-H2AX expression after exposure to IR. Results: As compared to THLE-2 cells, PAK7 was upregulated in poorly differentiated Mahlavu and SK-Hep-1 cells, but moderately or lowly expressed in well-differentiated Huh7 and HepG2 cells. HCC cells with moderate or low expression of PAK7 presented a decreased viability at 2 Gy IR, which had no significant effect on PAK7high HCC cells. Mahlavu and Huh7 cells transfected with PAK7 shRNAs showed increased inhibitory effect of IR on viability. In addition, PAK7 shRNAs reduced clone formation, facilitated the cell apoptosis, arrested cells at G2/M phase, and increased γ-H2AX expression. Moreover, changes above were more evident in the HCC cells co-treated with IR and PAK7 shRNAs. Conclusion: PAK7 downregulation could inhibit the viability, promote the apoptosis, arrest cells in G2/M phase, and induce the DNA damage in HCC cells, thereby enhancing the radiosensitivity in HCC.

Discovery and verification of mmu_Circ_26986/hsa_Circ_0072463 as a potential biomarker and intervention target for sepsis-associated acute kidney injury

“…6 ). Previous studies have reported that PAK7 exerts an antiapoptotic function in multiple tumor cell lines [ 43 – 45 ]. Similarly, our findings show that PAK7 knockdown enhances LPS-induced apoptosis in BUMPT cells through the Wnt/β-catenin pathway (Fig.…”

Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity

“…PAK5 and ABCB1 are positively correlated in HCC patient samples [103]. In HCC, cells expressing high PAK7 are resistant to radiation and enhance radiosensitivity through increasing H2AX [104] In lung cancer cells, PAK5 interacts with Sox2 and phosphorylates Sox2. It also regulates the other stem cell markers such as ALDH, Nanog, Oct3/4, and Sox2 [105].…”

Radiotherapy modulates tumor cell fate decisions: a review

“…Radiation-induced senescence is mainly controlled by the activation of the p53-p21 pathway and the p16 INK4a -retinoblastoma protein (pRB) pathway [14,100]. After ionizing radiation damages tumor cell DNA, activated p53 upregulates the expression of p21, a cyclin-dependent kinase (CDK) inhibitor that inhibits the expression of CDK-cyclin complexes [101][102][103]. Inhibition of CDK1-cyclin A complex arrests cells in the G2/M phase [101,103].…”