Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells Academic Article uri icon

Overview

MeSH Major

  • BCG Vaccine
  • Pinocytosis
  • Urinary Bladder Neoplasms
  • p21-Activated Kinases

abstract

  • Bacille Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that is used widely as a vaccine for tuberculosis and is used as an effective treatment for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, its mechanism of action and response determinants remain obscure. Here, we establish a model system to analyze BCG interaction with bladder cancer cells, using it to show that these cells vary dramatically in their susceptibility to BCG infection. Unexpectedly, the uptake of BCG by bladder cancer cells occurs by macropinocytosis rather than phagocytosis. BCG entry into bladder cancer cells relied upon Rac1, Cdc42, and their effector kinase Pak1. The difference in susceptibility between BCG-permissive and -resistant bladder cancer cells was due to oncogenic activation of signaling pathways that activate macropinocytosis, with phosphoinositide 3-kinase inhibitor activation stimulating BCG uptake independently of Akt. Similarly, activated Ras strongly activated Pak1-dependent uptake of BCG. These results reveal that oncogenic activation of macropinocytosis determines BCG uptake by bladder cancer cells, implying that tumor responsiveness to BCG may be governed by the specific mutations present in the treated cancer cell.

publication date

  • February 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3756537

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-12-1882

PubMed ID

  • 23378476

Additional Document Info

start page

  • 1156

end page

  • 67

volume

  • 73

number

  • 3