Tobacco Smoke Activates Protein Association and Tyrosine Phosphorylation of the GPI-Transamidase Complex Subunits in Human Cancers

Abstract

We previously found that the protein subunits of GPI-transamidase complex (e.g. PIG-U, PIG-T and GPAA1) play critical roles of oncogenes in human bladder and breast cancers manifesting their activities through signaling mecha- nisms that involve urokinase receptor/Stat3 and paxillin pathways. We report here that cigarette smoke extract (CSE) en- hanced colony formation and invasiveness of certain human cancer cells (e.g. head and neck, bladder or breast). We found that CSE induced the complex formation between PIG-U, PIG-T and GPAA1 proteins and also the association between GPAA1 and EGFR in cancer cells. We observed that inhibitors of EGFR tyrosine kinase, Gefitinib or Erlotinib, modu- lated tyrosine phosphorylation of PIG-U and PIG-T induced by CSE. We also found that EGFR tyrosine kinase inhibitors and siRNA silencing of PIG-U, PIG-T or GPAA1 modulated the CSE-induced increase in colony formation and invasive- ness of human bladder cancer cells. We suggest that the novel mechanism overlapping the oncogenic potential of PIG-U, PIG-T and GPAA1 implicates EGFR tyrosine phosphorylation of PIG-U or PIG-T and subsequent paxillin phosphoryla- tion.