UCSD. US: Upending decades-old dogma, a team of scientists at the University of
California, San Diego School of Medicine say enzymes long categorized
as promoting cancer are, in fact, tumor suppressors and that current
clinical efforts to develop inhibitor-based drugs should instead focus
on restoring the enzymes’ activities.
The findings are published in the January 29 issue of Cell.
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 tumor-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 tumorigenesis.
“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 Alexandra Newton, PhD,
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
tumor growth.
Using live cell imaging, first author Corina Antal, a graduate
student in the Biomedical Sciences program at UC San Diego,
characterized 8 percent 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, tumor 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 signaling
increases, fueling tumor 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 tumors have arisen?
Long-term activation of PKCs by phorbol esters results in their
degradation, said first author Antal. In models of tumor 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 tumor-promoting
function may arise because a brake to oncogenic signaling has been
removed.”
Co-authors include Emily Kang, UCSD; Andrew M. Hudson, Christopher
Wirth, Crispin J. Miller, Natalie L. Stephenson, Eleanor W. Trotter and
John Brognard, University of Manchester, UK; Ciro Zanca and Frank B.
Furnari, Ludwig Cancer Research, UCSD; Lisa L. Gallegos, UCSD and
Harvard Medical School; and Tony Hunter, Salk Institute.
Funding for this research comes, in part, from the National
Institutes of Health (grants GM43154, NS080939, CA82683), the James S.
McDonnell Foundation, UCSD Graduate Training Program in Cellular and
Molecular Pharmacology, the National Science Foundation Graduate
Research Fellowship and Cancer Research UK.