Ovarian cancer is frequently diagnosed after the disease has already spread to other parts of the body, leaving patients with a five-year survival rate of under 30 percent, according to researchers at the University of Maryland, Baltimore County (UMBC). Standard therapies often inflict heavy damage on healthy cells alongside malignant cells. New research published September 17 in Molecular Therapy Oncology highlights an enzyme called USP15 as a promising molecular target for precision cancer drugs that could spare healthy cells.
The Role of USP15 in Ovarian Cancer Progression
Biological sciences Ph.D. student Ayokunnumi “Ayo” Ogunsanya led the study, conducting experiments in both cells and mice. The findings demonstrate that lowering levels of the USP15 enzyme triggers a constellation of effects in ovarian cancer cells. Specifically, it slows cancer-cell growth, disrupts chromosome separation during division to induce DNA damage and cell death, curtails the ability of cells to migrate and invade other tissues, and increases sensitivity to common chemotherapy drugs.
Did you know? Two-thirds of p53 mutations in ovarian cancer act like a stuck accelerator rather than a disabled brake, actively enhancing cancer progression while lingering in the cell far longer than normal.
A Serendipitous Discovery Involving p53 Mutations
The discovery stemmed from earlier work by Achuth Padmanabhan as a postdoctoral fellow at Baylor College of Medicine. Padmanabhan investigated the p53 protein, which typically prevents tumor formation. Mutations in the gene coding for p53 appear in nearly every case of the most common and lethal form of ovarian cancer.
Padmanabhan found that the USP15 enzyme stabilizes a specific p53 mutant by removing small molecular tags that normally mark proteins for degradation. With abundant USP15 present, fewer mutant proteins face destruction. When Padmanabhan joined UMBC as an assistant professor in 2019, he expanded this line of inquiry, and Ogunsanya joined his lab in 2021 to focus her Ph.D. research on USP15’s role in ovarian cancer.
Enhancing Chemotherapy Vulnerability
Lowering USP15 levels made cancer cells more vulnerable to standard treatment drugs, including carboplatin, paclitaxel, and the particularly toxic doxorubicin. According to the research team, reducing USP15 could allow lower doses of these chemotherapies to achieve the same treatment effect with reduced toxicity.
Reaching these conclusions required rigorous re-evaluation. Early findings showed a molecule associated with cell growth rising instead of falling when USP15 decreased. Further analysis revealed that a separate cell division molecule dropped, indicating that while cancer cells kept growing with less USP15, they failed to successfully divide because duplicated chromosomes did not separate properly.
Future Directions for Drug Development
Padmanabhan’s team aims to uncover the basic functionality controlling USP15 levels within cancer cells and determine whether inhibiting the enzyme reshapes a tumor’s immediate surroundings. Because molecules capable of inhibiting USP15 in laboratory experiments already exist, researchers have a viable starting point for translational drug development.
“Hopefully, work such as ours demonstrating the potential of USP15 as an anti-cancer therapeutic target will motivate pharmaceutical companies and other research groups to pursue the development of clinically translatable USP15 inhibitors,” Padmanabhan said.
Frequently Asked Questions
What is USP15?
USP15 is an enzyme that ovarian cancer cells rely on more heavily than normal cells. It stabilizes specific cancer-promoting proteins by preventing their degradation.
How does lowering USP15 affect cancer cells?
Lowering USP15 slows cancer cell growth, prevents proper chromosome separation during division—leading to cell death—reduces tissue invasion, and increases sensitivity to chemotherapy.
Which chemotherapy drugs become more effective?
Research shows that reducing USP15 increases cancer cell vulnerability to carboplatin, paclitaxel, and doxorubicin.
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