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Atypical Protein Kinase C Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida

Requests for reprints: Alan P. Fields, Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224. Phone: 904-953-6160; Fax: 904-953-0277; E-mail: fields.alan{at}mayo.edu.

Key Words: mechanism-based therapy • anchorage-independent growth • tumorigenicity • small cell lung cancer • non–small cell lung cancer

The antirheumatoid agent aurothiomalate (ATM) is a potent inhibitor of oncogenic PKC. ATM inhibits non–small lung cancer (NSCLC) growth by binding PKC and blocking activation of a PKC-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 IC₅₀s ranging from 300 nmol/L to >100 µmol/L. ATM sensitivity correlates positively with expression of PKC and Par6, but not with the PKC binding protein p62, or the proposed targets of ATM in rheumatoid arthritis (RA), thioredoxin reductase 1 or 2. PKC expression profiling revealed that a significant subset of primary NSCLC tumors express PKC 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 and Par6. Our results indicate that PKC expression profiling will be useful in identifying lung cancer patients most likely to respond to ATM therapy in an ongoing clinical trial. [Cancer Res 2008;68(14):5888–95]

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