Details

Autor(en) / Beteiligte

• Antal, Corina E.
• Hudson, Andrew M.
• Kang, Emily
• Zanca, Ciro
• Wirth, Christopher
• Stephenson, Natalie L.
• Trotter, Eleanor W.
• Gallegos, Lisa L.
• Miller, Crispin J.
• Furnari, Frank B.
• Hunter, Tony
• Brognard, John
• Newton, Alexandra C.

Titel

Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor

Ist Teil von

• Cell, 2015-01, Vol.160 (3), p.489-502

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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. [Display omitted] •Cancer-associated PKC mutations are LOF and can act in a dominant-negative manner•Correcting a heterozygous PKCβ LOF mutation reduces tumor volume•Hemizygous deletion shows PKC is haploinsufficient for tumor suppression•Therapeutic strategies should aim to restore PKC activity instead of inhibiting it Cancer-associated kinase mutations have generally been characterized as oncogenic, but an analysis of PKC mutations reveals that the majority are loss of function, indicating a tumor-suppressive role for this kinase and a shift in therapeutic strategies targeting PKC.