Abstract
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 tissues were 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 STAT3 induced G0/G1 arrest and inhibited adhesion in J82 cells. 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 J82 cells 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 apoptosis in 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 overcoming such resistance.
Keywords: Adhesion, bladder cancer, diindolylmethane, migration, prevention, STAT
Current Cancer Drug Targets
Title:Inhibition of STAT Signalling in Bladder Cancer by Diindolylmethane - Relevance to Cell Adhesion, Migration and Proliferation
Volume: 13 Issue: 1
Author(s): Yiyang Sun, Mai-Kim Cheng, Thomas. R.L.Griffiths, J. Kilian Mellon, Bao Kai, Marina Kriajevska and Margaret M. Manson
Affiliation:
Keywords: Adhesion, bladder cancer, diindolylmethane, migration, prevention, STAT
Abstract: 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 tissues were 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 STAT3 induced G0/G1 arrest and inhibited adhesion in J82 cells. 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 J82 cells 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 apoptosis in 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 overcoming such resistance.
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Cite this article as:
Sun Yiyang, Cheng Mai-Kim, R.L.Griffiths Thomas., Kilian Mellon J., Kai Bao, Kriajevska Marina and M. Manson Margaret, Inhibition of STAT Signalling in Bladder Cancer by Diindolylmethane - Relevance to Cell Adhesion, Migration and Proliferation, Current Cancer Drug Targets 2013; 13 (1) . https://dx.doi.org/10.2174/1568009611309010057
DOI https://dx.doi.org/10.2174/1568009611309010057 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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