Src and Caveolin-1 Reciprocally Regulate Metastasis via a Common Downstream Signaling Pathway in Bladder Cancer

Abstract

In bladder cancer, increased Caveolin-1 (Cav-1) expression and decreased Src expression and kinase activity correlate with tumor aggressiveness. Here, we investigate the clinical and functional significance if any, of this reciprocal expression in bladder cancer metastasis. We evaluated the ability of tumor Cav-1 and Src RNA and protein expression to predict outcome following cystectomy in 257 patients enrolled in two independent clinical studies. In both, high Cav-1 and low Src levels were associated with metastasis development. We overexpressed or depleted Cav-1 and Src protein levels in UMUC-3 and, RT4 human bladder cancer cells and evaluated the effect of this on actin stress fibers, migration using transwells and lung metastasis following tail vein inoculation. Cav-1 depletion or expression of active Src in metastatic UMUC-3 cells decreases actin stress fibers, cell migration and metastasis, while, Cav-1 overexpression or Src depletion increased the migration of non-metastatic RT4 cells. Biochemical studies indicated Cav-1 mediates these effects via its phosphorylated form (pY14), whereas Src effects are mediated through phosphorylation of p190RhoGAP and these pathways converge to reduce activity of RhoA, RhoC and Rho effector ROCK1. Treatment with a ROCK inhibitor reduced UMUC-3 lung metastasis in vivo, phenocopying the effect of Cav-1 depletion or expression of active Src. Src suppresses while Cav-1 promotes metastasis of bladder cancer through a pharmacologically tractable common downstream signaling pathway. Clinical evaluation of personalized therapy to suppress metastasis development based on Cav-1 and Src profiles appears warranted.

Transcriptional Repression of Caveolin-1 (CAV1) Gene Expression by GATA-6 in Bladder Smooth Muscle Hypertrophy in Mice and Human Beings

“…52 Caveolin-1 expression is correlated with tumor stage and grade of bladder transitional cell carcinoma (TCC). 53,54 Caveolin-1 expression was correlated significantly with T stage and grade of bladder TCC, which strongly indicates that caveolin-1 is involved in tumor progression and that the increased expression of caveolin-1 is a late event in urothelial carcinomas. 55 The increased expression of caveolin-1 is associated with tumor progression and poor prognosis in Figure 11.…”

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

“…ITGA4 is a good example. Even classical proto-oncogene c-src, whose activity or expression is elevated in a number of human tumors, suppresses metastasis of bladder cancer (56,57). Future work should therefore include metastatic models of carcinomas to evaluate whether HOPX is universally associated with metastasis.…”

Downregulation of caveolin-1 increases the sensitivity of drug-resistant colorectal cancer HCT116 cells to 5-fluorouracil

“…Cav-1 acts as a scaffolding protein by interacting with signaling molecules through a caveolin scaffolding domain to modulate gene expression, signal transduction and protein translocation in the cell membrane (18 invasion and metastasis (19)(20)(21)(22). Additionally, it has been shown that Cav-1 is closely associated with the development of drug resistance (23)(24)(25).…”