Cytotoxic necrotizing factor 1 promotes bladder cancer angiogenesis through activating RhoC

Abstract

Uropathogenic Escherichia coli (UPEC), a leading cause of urinary tract infections, is associated with prostate and bladder cancers. Cytotoxic necrotizing factor 1 (CNF1) is a key UPEC toxin; however, its role in bladder cancer is unknown. In the present study, we found CNF1 induced bladder cancer cells to secrete vascular endothelial growth factor (VEGF) through activating Ras homolog family member C (RhoC), leading to subsequent angiogenesis in the bladder cancer microenvironment. We then investigated that CNF1‐mediated RhoC activation modulated the stabilization of hypoxia‐inducible factor 1α (HIF1α) to upregulate the VEGF. We demonstrated in vitro that active RhoC increased heat shock factor 1 (HSF1) phosphorylation, which induced the heat shock protein 90α (HSP90α) expression, leading to stabilization of HIF1α. Active RhoC elevated HSP90α, HIF1α, VEGF expression, and angiogenesis in the human bladder cancer xenografts. In addition, HSP90α, HIF1α, and VEGF expression were also found positively correlated with the human bladder cancer development. These results provide a potential mechanism through which UPEC contributes to bladder cancer progression, and may provide potential therapeutic targets for bladder cancer.

Prevalence of Cyclomodulin-Positive E. coli and Klebsiella spp. Strains in Mexican Patients with Colon Diseases and Antimicrobial Resistance

“…cnf is a cyclomodulin that promotes cellular proliferation by stimulating the assembly of actin stress fibers and focal adhesions by deamination and DNA synthesis, and cnf has only been found in E. coli and Y. pseudotuberculosis. Although cnf has been associated with uropathogenic E. coli and bladder cancer, in this study, cnf was found in DEC and non-DEC, and primarily in CRC patients [26]. A previous report detected cnf-1 in stool samples for the first time, but only one sample was positive for this genotoxin from healthy people in Puerto Rico.…”

Effects of the Escherichia coli Bacterial Toxin Cytotoxic Necrotizing Factor 1 on Different Human and Animal Cells: A Systematic Review

“…In most studies, the induction of at least some of the morphological effects characteristic of Rho GTPase activation is described, that is, changes in the actin cytoskeleton organization, demonstrated by actin stress fibers or the formation of actin cables, membrane ruffles, filopodia and lamellipodia assembly (Figure 2A) [6][7][8]10,25,26,32,[34][35][36]38,40,41,[44][45][46][47][50][51][52]56,94,95]. Regardless of the method used to identify the impact of CNF1-induced cytoskeletal modifications on cell movement ability (migration-invasion test, scratch wound healing assay), CNF1 treatment stimulated an increase of cell motility in 13 cell lines (T24, 5637, HUVEC [28]; HT-29, SW480, HEp-2 [22]; PC3, LNCaP, 22Rv1, VCaP [62]; BL6-10 [64]; 804G, HUVEC [8]; T-lymphocytes [44]). Among these, in PC3 [62] and BL6-10 [64] cells, this effect was accompanied by an in vivo increase in metastatic ability.…”

“…Both Rho GTPases and cytoskeletal rearrangements are also known to influence gene transcription [93]. Actually, after CNF1 intoxication, in 17 cell lines (HeLa [38]; BL6-10 [65]; HEp-2 [48,52]; GL-261 [31]; C2C12 [76]; HUVEC [10]; 3T3-L1 [75]; mouse peritoneal macrophages, Raw264.1, BMDM, THP-1 [96]; 5637, T24 [28]; HT-29, IEC-6 [22]; 293T [68]) a number of transcription factors (TFs) also result in being modulated. For example, in HEp-2 epithelial cells, CNF1 activates NF-κB through the Rac1/PI3K/Akt/IKK prosurvival pathway, with the ensuing modulation of the antiapoptotic proteins Bcl-2 and Bcl-XL [51,95].…”

“…One more example shows how, in both 5637 and T24 uroepithelial cell lines, under hypoxic conditions, CNF1 indirectly promotes VEGF secretion and angiogenesis through RhoC-dependent activation of the HSF1-HSP90α-HIF1α axis. In particular, activated RhoC induces HIF1α stabilization and VEGF production by increasing HSP90α expression and the interaction between HIF1α and HSP90 [28]. Beyond the mentioned examples, other TFs, as well as proteins, are described in the literature as modulated after CNF1 cell treatment (IκB-α, c-Jun [10]; MyoD [76]; C/EBP-α, PPAR-γ [75]; AP-1 [38]; FoxG1 [31]; C/EBP-α, LXR-β [96]; Snail1, ZEB1 [22]).…”

Role of RhoC in cancer cell migration

“…RhoC reportedly affects cell movement by influencing the activities of actin and myosin, and cell adhesion [ 35 ], thereby affecting the process of cancer metastasis. According to the existing literature, it plays an important role in many cancers, such as influencing angiogenesis in bladder cancer [ 36 ] and tumorigenesis and epithelial-mesenchymal transition (EMT) in osteosarcoma [ 37 ], regulating the emergence of radioresistance in cervical cancer [ 38 ], and affecting prostate cancer treatments that target the glutamine pathway [ 39 ]. Certainly, its most significant role is promoting metastasis in breast [ 40 – 42 ], gastric [ 43 , 44 ], colon [ 45 , 46 ], bladder [ 47 ], prostate [ 48 , 49 ], lung [ 50 ], pancreatic [ 51 ], liver [ 52 ] and other cancers.…”