Upending decades-old dogma, a team of scientists at the University of California, San Diego School of Medicine say enzymes long categorised as promoting cancer are, in fact, tumour suppressors and that current clinical efforts to develop inhibitor-based drugs should instead focus on restoring the enzymes' activities.
Protein Kinase C (PKC) is a group of enzymes that act as catalysts for a host of cellular functions, among which are cancer-relevant activities, such as cell survival, proliferation, apoptosis, and migration. The discovery that they are receptors for tumour-producing phorbol esters, plant-derived compounds that bind to and activate PKC, created a dogma that activation of PKCs by phorbol esters promoted carcinogen-induced tumourigenesis.
"For three decades, researchers have sought to find new cancer therapies based on the idea that inhibiting or blocking PKC signals would hinder or halt tumor development," said Dr Alexandra Newton, professor of pharmacology and the study’s principal investigator, "but PKCs have remained an elusive chemotherapeutic target." The reason, suggest Newton and colleagues, is that contrary to conventional wisdom, PKCs do not promote cancer progression; rather, they act to suppress tumour growth.
Using live cell imaging, first author Corina Antal, a graduate student in the Biomedical Sciences programme at UC San Diego, characterised 8% of the more than 550 PKC mutations identified in human cancers. This led to the unexpected discovery that the majority of mutations actually reduced or abolished PKC activity, and none were activating. The mutations impeded signal binding, prevented correct structuring of the enzyme, or impaired catalytic activity.
When the scientists corrected a loss-of-function PKC mutation in the genome of a colon cancer cell line, tumour growth in a mouse model was reduced, demonstrating that normal PKC activity inhibits cancer. One possible explanation, said the researchers, is that PKC typically represses signaling from certain oncogenes – genes that can cause normal cells to become cancerous. When PKC is lost, oncogenic signalling increases, fuelling tumour growth.
"Inhibiting PKC has so far proved not only an unsuccessful strategy in a number of cancer clinical trials, but its addition to chemotherapy has resulted in decreased response rates in patients," said Newton. "Given our results, this isn't surprising. Our findings suggest therapeutic strategies need to go the other way and target ways to restore PKC activity, not inhibit it. This is contrary to the current dogma."
How could this misconception of PKC promoting tumours have arisen? Long-term activation of PKCs by phorbol esters results in their degradation, said first author Antal. In models of tumour promotion, a sub-threshold dose of a carcinogen is painted on mouse skin, followed by repeated applications of phorbol esters. "This repeated application of phorbol esters will lead to the loss of PKC. Thus, their tumour-promoting function may arise because a brake to oncogenic signalling has been removed."
[link url="http://ucsdnews.ucsd.edu/pressrelease/enzymes_believed_to_promote_cancer_actually_suppress_tumors"]University of California, San Diego School of Medicine release[/link]
[link url="http://www.cell.com/chemistry-biology/abstract/S1074-5521(14)00423-2"]Cell article summary[/link]