P21-Activated Kinase 7 Mediates Cisplatin-Resistance of Esophageal Squamous Carcinoma Cells with Aurora-A Overexpression

Abstract

Aurora-A overexpression is common in various types of cancers and has been shown to be involved in tumorigenesis through different signaling pathways, yet how the deregulation affects cancer therapeutics remains elusive. Here we showed that overexpression of Aurora-A rendered esophageal cancer cells resistance to cisplatin (CDDP) by inhibiting apoptosis. By using an apoptosis array, we identified a downstream gene, p21-activated kinase 7 (PAK7). PAK7 was upregulated by Aurora-A overexpression at both mRNA and protein levels. Importantly, the expression levels of Aurora-A and PAK7 were correlated in ESCC primary samples. Chromatin immunoprecipitation (ChIP) assay revealed that binding of E2F1 to the promoter of PAK7 was significantly enhanced upon Aurora-A activation, and knockdown of transcription factor E2F1 decreased PAK7 expression, suggesting that Aurora-A regulated PAK7 through E2F1. Furthermore, we demonstrated that PAK7 knockdown led to increased apoptosis, and Aurora-A-induced resistance to CDDP was reversed by downregulation of PAK7, suggesting PAK7 was a downstream player of Aurora-A that mediated chemoresistance of ESCC cells to CDDP. Our data suggest that PAK7 may serve as an attractive candidate for therapeutics in ESCC patients with Aurora-A abnormality.

Structure, biochemistry, and biology of PAK kinases

“…PAK5, also known as PAK7, is upregulated by Aurora-A (He et al, 2014) and downregulated by miR-129 and miR-186 in certain cancer cells (Zhai J et al, 2015; Zheng J et al, 2015). Studies from Pak5- knockout mice show PAK5 has roles in mobility, learning, and memory related functions (Nekrasova et al, 2008; Furnari et al, 2013).…”

“…Similar to PAK1, upregulation of PAK4 promotes insensitivity to chemotherapies such as doxorubicin or paclitaxel (Park et al, 2013), cisplatin (Shu et al, 2015; Fu et al, 2014) in different cancer types, and gemcitabine in cancer cells (Moon et al, 2015). Likewise, PAK5 overexpression confers resistance to paclitaxel (Li et al, 2013) and cisplatin in cancer cells (He et al, 2014; Zhang et al, 2015). PAK6 overexpression promotes therapeutic resistance to 5-fluorouracil in some patients (Chen et al, 2015).…”

MicroRNA-492 overexpression exerts suppressive effects on the progression of osteosarcoma by targeting PAK7

“…It has been previously demonstrated that PAK7 can support cell mobility and proliferation by activating survival pathways (11). The apoptotic signaling is also inhibited due to the mitochondria localization of PAK7 (40). In OS cells, the knockdown of PAK7 can also favor the induction of apoptosis.…”

“…It can de-sensitize the apoptotic potential induced by camptothecin and C2-ceramide by phosphorylating BAD, a pro-apoptotic member of the BCL-2 family at Ser-112 (11). PAK7 has also been shown to mediate cisplatin resistance and contributes to the progression of esophageal cancer (40). The mechanism was largely ascribed to the E2F1-induced transcriptional upregulation of PAK7 via Aurora-A activation (40).…”

“…PAK7 has also been shown to mediate cisplatin resistance and contributes to the progression of esophageal cancer (40). The mechanism was largely ascribed to the E2F1-induced transcriptional upregulation of PAK7 via Aurora-A activation (40). PAK7 has also been shown to serve as a biomarker for the proliferation of pancreatic cancer cell xenografts (12).…”