Effective treatments to prevent recurrence or progression of non-muscle-invasive bladder cancer, or to inhibit metastasis of muscle-invasive forms of the disease, would deliver significant patient benefit.
Here the involvement of STAT signalling and the chemopreventive potential of diindolylmethane (DIM) in human bladder cancer were investigated. Muscle-invasive bladder cancer tissueswere characterised by nuclear expression of phosphorylated STAT1, 3 and 5. In E-cadherin positive tumour cell lines (RT112, RT4, HT1376), STAT5 was constitutively phosphorylated, while E-cadherin negative lines (J82, T24, UMUC3) contained phosphoSTAT3. Knockdown of STAT3induced G0/G1 arrest and inhibited adhesion in J82cells, Knockdown of STAT1inhibited migration in J82 and RT112 lines. No significant increase in apoptosis was observed. In response to the Janus kinase inhibitor, AG490, RT112 and J82 cells initially underwent G0/G1 arrest,with RT112 cells subsequently exhibiting S phase arrest. Phosphorylation of STAT1Tyr701, STAT3Tyr705 and Ser727 and STAT5Tyr694 was inhibited by DIM, as was adhesion of J82cells to collagen, an effect that was enhanced when STAT1 or 3 was reduced by siRNA. However, over-expression of STAT3C partially rescued the DIM inhibitory effect on collagen-mediated adhesion. Migration of both lines was inhibited by DIM, while transfection of constitutively active STAT3C enhanced migration of RT112 cells. DIM induced cell cycle arrest and apoptosisin three cell lines with different degrees of radioresistance. Taken together, these results suggest that inhibition of STAT signalling and/or treatment with DIM may decrease invasiveness of bladder cancer. DIM can induce apoptosis in cell lines which are radioresistant, so in combination with radiotherapy may be useful in overcomingsuch resistance.
Written by:
Sun Y, Cheng MK, Griffiths TR, Mellon JK, Kai B, Kriajevska M, Manson MM. Are you the author?
Department of Cancer Studies and Molecular Medicine, Biocentre, University of Leicester, LE1 7RH, UK.
Reference: Curr Cancer Drug Targets. 2012 Aug 16. Epub ahead of print.
PubMed Abstract
PMID: 22920439
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