Atypical protein kinase C iota expression and aurothiomalate sensitivity in human lung cancer cells.
The antirheumatoid agent aurothiomalate (ATM) is a potent inhibitor of oncogenic PKC iota. ATM inhibits non-small lung cancer (NSCLC) growth by binding PKC iota and blocking activation of a PKC iota-Par6-Rac1-Pak-Mek 1,2-Erk 1,2 signaling pathway. Here, we assessed the growth inhibitory activity of ATM in a panel of human cell lines representing major lung cancer subtypes. ATM inhibited anchorage-independent growth in all lines tested with IC(50)s ranging from approximately 300 nmol/L to >100 micromol/L. ATM sensitivity correlates positively with expression of PKC iota and Par6, but not with the PKC iota binding protein p62, or the proposed targets of ATM in rheumatoid arthritis (RA), thioredoxin reductase 1 or 2. PKC iota expression profiling revealed that a significant subset of primary NSCLC tumors express PKC iota at or above the level associated with ATM sensitivity. ATM sensitivity is not associated with general sensitivity to the cytotoxic agents cis-platin, placitaxel, and gemcitabine. ATM inhibits tumorigenicity of both sensitive and insensitive lung cell tumors in vivo at plasma drug concentrations achieved in RA patients undergoing ATM therapy. ATM inhibits Mek/Erk signaling and decreases proliferative index without effecting tumor apoptosis or vascularization in vivo. We conclude that ATM exhibits potent antitumor activity against major lung cancer subtypes, particularly tumor cells that express high levels of the ATM target PKC iota and Par6. Our results indicate that PKC iota expression profiling will be useful in identifying lung cancer patients most likely to respond to ATM therapy in an ongoing clinical trial.
Regala
Roderick P
RP
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA.
Thompson
E Aubrey
EA
Fields
Alan P
AP
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006052:Gold Sodium Thiomalate / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000235:genetics*; D000099293:Protein Kinase C-lambda
D018501:Antirheumatic Agents; D006052:Gold Sodium Thiomalate; D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda