Cytotoxic necrotizing factor 1 promotes prostate cancer progression through activating the Cdc42–PAK1 axis

Abstract

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and plays a role in prostatic carcinogenesis and prostate cancer (PCa) progression. However, the mechanisms through which UPEC promotes PCa development and progression are unclear. Cytotoxic necrotizing factor 1 (CNF1) is one of the most important UPEC toxins and its role in PCa progression has never been studied. We found that UPEC-secreted CNF1 promoted the migration and invasion of PCa cells and PCa metastasis. In vitro studies showed that CNF1 promotes pro-migratory and pro-invasive activity through entering PCa cells and activating Cdc42, which subsequently induced PAK1 phosphorylation and up-regulation of MMP-9 expression. CNF1 also promoted pulmonary metastasis in a xenograft mouse model through these mechanisms. PAK1 phosphorylation correlated with advanced grades of PCa in human clinical PCa tissues. These results suggest that CNF1 derived from UPEC plays an important role in PCa progression through activating a Cdc42-PAK1 signal axis and up-regulating the expression of MMP-9. Therefore, surveillance for and treatment of cnf1-carrying UPEC strains may diminish PCa progression and thus have an important clinical therapeutic impact. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cytotoxic necrotizing factor 1 promotes bladder cancer angiogenesis through activating RhoC

“…We first examined the effects of CNF1 on the migration and invasion abilities of bladder cancer cells. We purified and validated CNF1 and C866S (an inactive mutant of CNF1) recombinant proteins from UPEC strain as we previously described, 6 and treated bladder cancer cell lines 5637 and T24. The Transwell assay showed that wild‐type CNF1 markedly enhanced the migration and invasion of T24 and 5637 cells.…”

“…For example, CNF1 promotes bacterial invasion into host cells by activating Rac 37 . Previously, we reported that CNF1 increased prostate cancer cell migration and invasion to promote prostate cancer metastasis through activating Cdc42, 6 and CNF1 reduced macrophage phagocytosis to induce inflammation during acute UTIs partially through Cdc42 38 . Schmidt reported that CNF1 enhanced breast cancer cell invasion through activating RhoC 39 …”

“…Recombinant proteins of CNF1 and its mutant C866S were expressed, purified, and identified as described previously 6 …”

“…In addition, UPEC was also reported to accelerate the prostate cancer progression in the genetically engineered Hi‐Myc mouse prostate cancer model, and increase the risk of bladder cancer through promoting CDKN2A methylation 4,5 . Previously, we reported that cytotoxic necrotizing factor 1 (CNF1), a key UPEC toxin, promoted migration and invasion of prostate cancer cells and prostate cancer metastasis by activating the Cdc42‐PAK1 Axis 6 . Although UPEC frequently infects bladder, the role of CNF1 in bladder cancer has not been reported.…”

Targeting Phosphorylation of p21-activated Kinase 1 at Thr423 Induces Cell Cycle Arrest and Apoptosis in Cutaneous T-cell Lymphoma Cells

“…Functional studies demonstrate that PAK1 plays a significant role in cell proliferation, motility, apoptosis, and tumor progression (5). Phosphorylated-PAK1 (pho-PAK1) is overexpressed in several malignancies, including extra-mammary Paget's disease, breast, prostate, and squamous cell carcinomas (9)(10)(11)(12). These findings indicate a pivotal role of pho-PAK1 in tumor pathogenesis.…”