Expression of phosphorylated p21-activated kinase 4 is associated with aggressive histologic characteristics and poor prognosis in patients with surgically treated renal cell carcinoma

Abstract

Purpose P21-activated kinase 4 (PAK4), a serine/threonine kinase that regulates a number of fundamental cellular processes, has been suggested as a prognostic factor for various human tumors. The aim of the present study was to evaluate the clinical implications of phospho-Ser474 PAK4 (pPAK4 S474 ), an activated form of PAK4, in surgically treated renal cell carcinoma (RCC). Materials and Methods Samples from 131 patients with surgically treated RCC were immunostained to detect PAK4 and pPAK4 S474 . Expression of PAK4 and pPAK4 S474 was compared with clinicopathological characteristics and survival after nephrectomy. Results PAK4 and pPAK4 S474 were expressed predominantly in the nucleus. Overall, 57.3% (75/131) and 24.4% (29/119) of specimens exhibited high expression of pPAK4 S474 and PAK4, respectively. High expression of pPAK4 S474 was associated with adverse pathologic characteristics, including advanced tumor stage and grade (p=0.036 and p=0.002, respectively), whereas this association was not significant for PAK4 expression (each p>0.05). Kaplan-Meier estimates showed that high expression of pPAK4 S474 was associated with shorter recurrence-free survival in a subgroup with localized RCC and with cancer-specific survival in the total RCC cohort (log-rank test: p=0.001 and p=0.005, respectively), whereas PAK4 expression was not. Multivariate Cox regression analysis identified that high pPAK4 S474 expression was an independent predictor of recurrence in the subgroup with localized RCC. Conclusions pPAK4 S474 may be a more accurate prognostic factor than total PAK4 in RCC patients. This marker would be useful for identifying patients with pathologically localized disease who may require further interventions.

p21‐activated kinase 4 inhibition protects against liver ischemia/reperfusion injury: Role of nuclear factor erythroid 2‐related factor 2 phosphorylation

“…On a molecular level, PAK4 phosphorylates Nrf2 at T369 and triggers its nuclear export and proteasomal degradation in the cytoplasm. A number of studies have reported PAK4 sion is positively correlated with pathological grade in several human cancers, [32,33] and I/R injury promotes HCC recurrence after LT. [34,35] inhibitor could be used not only to treat HCC per se, but also to reduce surgical morbidity and postoperative recurrence of HCC.…”