A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion.
Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCι and PKCζ are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCι/Par6 interaction, aurothiomalate, also disrupts PKCζ/Par6 interaction; 3) aurothiomalate inhibits downstream signaling of both PKCι and PKCζ, and blocks transformed growth of pancreatic cancer cells in vitro; and 4) aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo. Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non-redundantly by PKCι and PKCζ, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer.
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Amanda M
AM
Butler
Genoptix/Novartis Molecular Diagnostics, Carlsbad, CA, USA.
Michele L
ML
Scotti Buzhardt
Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Eda
E
Erdogan
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Shuhua
S
Li
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Kristin S
KS
Inman
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Alan P
AP
Fields
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Nicole R
NR
Murray
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D048868:Adaptor Proteins, Signal Transducing; D006052:Gold Sodium Thiomalate; D007527:Isoenzymes; D011493:Protein Kinase C; D034741:RNA, Small Interfering; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C499657:PARD6A protein, human
atypical PKCs; aurothiomalate; invasion; pancreatic cancer; transformed growth