Differential effects of MAPKs signaling on the growth of invasive bladder cancer cells

Int J Oncol. 2009 Jun;34(6):1557-64. doi: 10.3892/ijo_00000285.


Transitional cell carcinoma (TCC) is the most common form of bladder cancer. In bladder cancer, which in terms of its origins and genetics, is a representative of invasive tumors, the differing clinical course and the limited value of established prognostic markers compelled many researchers to look for new molecular parameters in predicting the prognosis and treatment of patients with bladder cancer. Activation of mitogen activated protein kinase (MAPK) is a frequent event in tumor progression and metastasis. In the current study, we investigated the role of two different MAPKs (ERK1/2 and p38) by using their specific inhibitors PD98059 and SB203580 respectively, on bladder cancer growth in two cell lines derived from different tumor stages. Our preliminary work showed that ERK1/2 and p38 MAP kinase are active during the log phase growth of bladder cancer, and inhibition of these pathways could reduce proliferation and growth. Moreover, treatment with these inhibitors hinders DNA synthesis, and has differential effects on the progression of cell cycle. ERK1/2 inhibitor caused cyclin B1-dependent G2/M arrest in both HTB5 and HTB9 bladder cancer cell lines, where as p38 MAPK inhibitor showed G2/M arrest in HTB9 and G1 arrest in HTB5 cell line. Furthermore, decreased proliferation and growth arrest caused by MAPK inhibitors was found to be a reflection of apoptotic induction by these inhibitors in bladder cancer cells. Thus, these studies establish MAPKs as a molecular target in bladder cancer growth which could provide new molecular modalities in clinical application.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Carcinoma, Transitional Cell / drug therapy
  • Carcinoma, Transitional Cell / metabolism
  • Carcinoma, Transitional Cell / pathology
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Enzyme-Linked Immunosorbent Assay
  • Flavonoids / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Immunoenzyme Techniques
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Pyridines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Flavonoids
  • Imidazoles
  • Pyridines
  • RNA, Messenger
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one