A study of high-grade ovarian cancer has shown the enzyme protein kinase C iota (PRKCI) to be an ovarian oncogene, suggesting PRKCI inhibition as a possible new therapeutic area of study for this deadly disease. The findings were published onlin in Genes & Development.
Ovarian cancer is the leading cause of death by cancers of the female reproductive system. Each year, approximately 22,000 women are diagnosed with the disease in the U.S.
“Our transgenic mouse model of ovarian cancer demonstrated that high PRKCI expression occurs early in ovarian cancer formation, and promotes an immune suppressive tumor microenvironment in cooperation with the protein YAP1,” says Sharmistha Sarkar, Ph.D., an instructor in Genomic Medicine at MD Anderson Cancer Center.
YAP1, or yes-associated protein, plays a role in tumor formation and has been considered a possible target for therapeutic intervention. YAP1 acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing cell-killing genes.
“Our study further provides insight regarding the oncogenic role of YAP1 in ovarian cancer,” says Giulio Draetta, M.D., a professor of Genomic Medicine at MD Anderson, and study co-lead investigator. “We found that YAP1 drives immune suppression in ovarian tumorigenesis. PRKCI and YAP1 together promote expression of immune suppressive genes such as TNFa. These findings are consistent with other studies implicating YAP1 in the regulation of genes in liver and prostate cancers.”
Tumor necrosis factor alpha (TNFa) is a cell signaling protein that plays a primary role in immune cell regulation and cell death. PRKCI appears to be linked to upregulation of TNFa.
“This results in an immune suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of T-cells,” explains Draetta. “We showed that high PRKCI expression correlates with high expression in TNFa and YAP1, and low infiltration of cancer-killing T cells. Thus, PRKCI-YAP regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.”