PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation

Abstract

P21-activated protein kinase1 (PAK1), a main downstream effector of small Rho GTPases, Rac1, and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Despite its importance, the molecular mechanisms of PAK1 that contributed to colorectal carcinogenesis remain unclear. Our immunohistochemistry showed that PAK1 expression was increased with colorectal cancer (CRC) progression through the adenoma to carcinoma sequence. Furthermore, our results suggested a relationship between PAK1 nuclear localization and the Dukes staging. In the present study, we showed that PAK1 knockdown decreased proliferation and delayed the G1/S cell-cycle transition, and increased apoptosis in vivo and in vitro. In addition, PAK1 knock-down downregulated c-Jun amino terminal kinases (JNK) activity and the levels of cyclinD1, CDK4/6. Inhibition of the JNK activity by chemical inhibitor (SP600125) significantly reduced the effects of PAK1 on CRC proliferation via accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In conclusion, our results demonstrate that knockdown of PAK1 could enhance the chemosensitivity of CRCs to 5-fluorouracil through G1 arrest. The mechanism by which PAK1 induced cancer growth might involve activation of JNK as well as downregulation of PTEN. Targeting PAK1 may represent a novel treatment strategy for developing novel chemotherapeutic agents.

Tracing PAKs from GI inflammation to cancer

“…Additionally, it was investigated if PAK1 knockdown and 5-FU synergistically inhibits tumour growth in a xenograft model. LoVo cells harbouring shPAK1 constructs were injected into nude mice and PAK1 knockdown significantly reduced tumour growth and proliferation 91. A further reduction in tumour growth was observed in combination with 5-FU.…”

“…PAK activation affects NF-κB,16 87 MAPK,89 – 91 PI3K92 and Wnt/β-catenin signalling13 linking inflammation and malignant transformation in the gut. Further, PAK signalling promotes epithelial–mesenchymal transition and invasiveness,1 3 93 both of which are common features of colitis-associated cancer (CAC).…”

“…Other investigations confirmed that both PAK1 and phospho-PAK1 were highly expressed in human and mouse CRC tissue samples105 111 (figure 5). Advanced CRC showed nuclear PAK1 expression indicative of poor patient prognosis 91. PAK4 mutations have also been identified in CRC; however, evidence is lacking to validate its role as driver of tumourigenesis 2 43.…”

“…Therefore, it is of great interest to investigate a possible synergism in PAK1 inhibition and 5-FU. Interestingly, in vitro, knockdown of PAK1 increased apoptosis in 5-FU treated LoVo cells 91. Additionally, it was investigated if PAK1 knockdown and 5-FU synergistically inhibits tumour growth in a xenograft model.…”

Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma

“…Therefore, our findings suggested that PAK1 plays a critical role in the proliferation of squamous-cell carcinomas. Several different downstream pathways have been shown to mediate oncogenic signaling related to PAK1 [19,20], but it is not clear which pathways regulate the progression of lung cancer. Recently, PAK4, a group-II PAK family member, was shown to promote prostate cancer progression through CREB [10].…”