Abstract
The p21-activated kinase 1 (PAK1), a serine/threonine kinase that orchestrates cytoskeletal remodeling and cell motility, has been shown to function as downstream node for various oncogenic signaling pathways to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, resulting in tumor formation and invasiveness. Although alterations in PAK1 expression and activity have been detected in various human malignancies, its potential biological and clinical significance in renal cell carcinoma (RCC) remains obscure. In this study, we found increased PAK1 and phosphorylated PAK1 levels in tumor tissues according to TNM stage progression. Elevated phosphorylated PAK1 levels associated with progressive features and indicated unfavorable overall survival (OS) as an independent adverse prognosticator for patients with RCC. Moreover, PAK1 kinase activation with constitutive active PAK1 mutant T423E promoted growth, colony formation, migration, invasion and stem-like phenotype of RCC cells, and vice versa, in PAK1 inhibition by PAK1 kinase inactivation with specific PAK1 shRNA, dead kinase PAK1 mutant K299R or allosteric inhibitor IPA3. Stem-like phenotype due to sunitinib administration via increased PAK1 kinase activation could be ameliorated by PAK1 shRNA, PAK1 mutant K299R and IPA3. Furthermore, nuclear factor-κB (NF-κB)/interleukin-6 (IL-6) activation was found to be responsible for PAK1-mediated stem-like phenotype following sunitinib treatment. Both IL-6 neutralizing antibody and IPA3 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that oncogenic activation of PAK1 defines an important mechanism for maintaining stem-like phenotype and sunitinib resistance through NF-κB/IL-6 activation in RCC, lending PAK1-mediated NF-κB/IL-6 activation considerable appeal as novel pharmacological therapeutic targets against sunitinib resistance.
Highlights
renal cell carcinoma (RCC) are detected incidentally by the widespread use of abdominal imaging examinations for unrelated symptoms, ∼ 25–30% of patients are still diagnosed with metastatic disease.[3]
As the bestcharacterized member of the p21-activated kinase (PAK) family, PAK1 was identified as a protein that interacts with cell division cycle 42 (CDC42) and RAC1.11 In addition to CDC42 and RAC1, other signaling including PI3K/Akt can lead to the activation of PAK1.12
The immunohistochemistry (IHC) staining results showed that expression levels of PAK1 and p-PAK1 were increased in tumor tissues compared with peritumoral tissues (Figure 1a)
Summary
RCCs are detected incidentally by the widespread use of abdominal imaging examinations for unrelated symptoms, ∼ 25–30% of patients are still diagnosed with metastatic disease.[3]. PAK1 is a component of various signaling pathways, including mitogenactivated protein kinase (MAPK), JUN N-terminal Kinase (JNK) and nuclear factor-κB (NF-κB) pathways, all of which are believed to be important in carcinogenesis.[9] PAK1 has been found to play critical roles in anoikis resistance that facilitates metastasis by allowing tumor cells to survive following detachment from the matrix in original tissue and travelling to distant sites. Resistance to anoikis program represents a molecular basis for cancer progression and drug resistance.[15,17] The regulation of phosphorylation and function of Snail by PAK1 signaling kinase may contribute to the process of epithelial–mesenchymal transition (EMT) that plays a pivotal role in the conversion of early-stage tumors into invasive malignancies.[18] EMT induction in cancer cells results in the acquisition of stem-like phenotype and drug resistance trait.[19,20]
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