PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy

Abstract

p21-Activated kinase 6 (PAK6) has been implicated in radiotherapy and docetaxel resistance. We have further evaluated PAK6 as a predictor of 5-fluorouracil (5-FU) treatment response in colon cancer. Here we report that in colon cancer PAK6 promotes tumor progression and chemoresistance both in vitro and in vivo. In the clinical analysis, PAK6 was overexpressed in 104 of 147 (70.75%) stage II and III patients who received 5-FU based chemotherapy after surgery. Multivariate Cox regression analysis indicated that PAK6 was an independent prognostic factor for overall survival (P < 0.001) and disease-free survival (P < 0.001). Colon cancer cell lines showed increased PAK6 expression upon 5-FU treatment. In PAK6-knockdown cells treated with 5-FU, cell viability and phosphorylation of BAD decreased, and the number of apoptotic cells, levels of cleaved caspase 3 and PARP increased compared to control cells. The opposite was observed in PAK6 overexpressing cells. Short hairpin RNA knockdown of PAK6 blocked cells in G2-M phase. Furthermore, Animal experiments results in vivo are consistent with outcomes in vitro. This study demonstrates that PAK6 is an independent prognostic factor for adjuvant 5-FU-based chemotherapy in patients with stage II and stage III colon cancer.

Structure, biochemistry, and biology of PAK kinases

“…As PAK6 is predominantly expressed in the brain, PAK6 has been recognized as a therapeutic candidate gene for epileptic encephalopathy (Oliver et al, 2016). PAK6 is upregulated in colon cancer (Chen et al, 2015), hepatocellular carcinoma (Chen et al, 2014), and prostate cancer (Kaur et al, 2008; Wen et al, 2009). However, PAK6 downregulation in clear renal cell carcinoma is associated with unfavorable survival of patients (Liu et al, 2014).…”

“…However, PAK6 downregulation in clear renal cell carcinoma is associated with unfavorable survival of patients (Liu et al, 2014). In human therapeutic treatments, PAK6 upregulation promotes resistance to 5- fluorouracil treatment in colon cancer patients (Chen et al, 2015), and its inhibition enhances the sensitivity of prostate cancer cells to radiation (Zhang et al, 2010) and docetaxel (Wen, et al, 2009). …”

“…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). These representative examples highlight the potential use of PAK-inhibitors in cancer chemotherapies to reverse resistance.…”

Tumor Suppressive Function of p21-activated Kinase 6 in Hepatocellular Carcinoma

“…Meanwhile, PAK6 was found to be induced by INPP4B to suppress prostate cells invasion (14). In colon cancer, PAK6 conferred chemoresistance for patients undergoing 5-fluorouracil based chemotherapy (15). In clearcell RCC, our former work indicated that PAK6 expression was decreased in the progress of clear-cell RCC and was an independent favorable clinical prognostic (16).…”

Gap junction composed of connexin43 modulates 5-fluorouracil, oxaliplatin and irinotecan resistance on colorectal cancers

“…Various types of therapeutic strategies have been used for the treatment of colon cancer, including radiotherapy, chemotherapy, targeted therapy, and immune therapy, however, the five-year survival rate of metastatic colon cancer remains <10% (2). Chemotherapy is one of the most commonly used therapeutic strategies for metastatic colon cancer, agents used include 5-fluorouracil (5-FU), oxaliplatin and irinotecan, however, development of resistance markedly limits their application in clinical use (3)(4)(5). For example, 5-FU, which has been used for many years, has a single agent effective rate of 24% (2).…”