title: Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells.
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.
authors: Infectious Diseases Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Gil
authors: G
authors: Redelman-Sidi
authors: Gopa
authors: G
authors: Iyer
authors: David B
authors: DB
authors: Solit
authors: Michael S
authors: MS
authors: Glickman
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D001500:BCG Vaccine / Q000378:metabolism* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002966:Clathrin / Q000502:physiology; D015638:Cytochalasin D / Q000494:pharmacology; D034281:Dynamins / Q000502:physiology; D006801:Humans; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010873:Pinocytosis; D019311:Staurosporine / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000628:therapy*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D054462:p21-Activated Kinases / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
chemical_list: D001500:BCG Vaccine; D002966:Clathrin; D015638:Cytochalasin D; D000584:Amiloride; D019869:Phosphatidylinositol 3-Kinases; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D034281:Dynamins; D019311:Staurosporine; C039614:ethylisopropylamiloride
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