Cancer-associated protein kinase C mutations reveal kinase’s role as tumor suppressor

Antal, C. E. et al. (2015) Cancer-associated protein kinase C mutations reveal kinase’s role as tumor suppressor. Cell, 160(3), pp. 489-502. (doi: 10.1016/j.cell.2015.01.001) (PMID:25619690) (PMCID:PMC4313737)

Abstract

Summary: Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands, phorbol esters, and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that, surprisingly, most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding, phosphorylation, or catalysis. Correction of a loss-of-function PKCβ mutation by CRISPR-mediated genome editing in a patient-derived colon cancer cell line suppressed anchorage-independent growth and reduced tumor growth in a xenograft model. Hemizygous deletion promoted anchorage-independent growth, revealing that PKCβ is haploinsufficient for tumor suppression. Several mutations were dominant negative, suppressing global PKC signaling output, and bioinformatic analysis suggested that PKC mutations cooperate with co-occurring mutations in cancer drivers. These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Miller, Professor Crispin
• Authors: Antal, C. E., Hudson, A. M., Kang, E., Zanca, C., Wirth, C., Stephenson, N. L., Trotter, E. W., Gallegos, L. L., Miller, C. J., Furnari, F. B., Hunter, T., Brognard, J., and Newton, A. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Published Online: 22 January 2015