The Role of p53 Synthetic Lethality in Increased Chemosensitivity to DNA-Damaging Agents Conferred by the Exercise Myokine Irisin
Abstract
Studies have shown that exercise is associated with a decreased risk of developing many types of cancer, including breast cancer. Interestingly, numerous studies have also shown that exercise post-diagnosis is associated with increased survival odds. For example, any level of exercise during the first 36 months post-breast cancer diagnosis is associated with a 30% decrease in cancer-related death and 40% decrease in recurrence, with a 66% decrease in cancer-related death in women with greatest physical activity. The benefits are similar or greater in magnitude to reductions in cancer-related death for medical interventions such as tamoxifen. Understanding the molecules linking exercise to improved patient outcome could lead to new therapeutics leveraging this knowledge. Physical activity’s molecular link with cancer prevention and survival has been hypothesized to be mediated through hormones, insulin, inflammation, and immune function. However, evidence directly linking these potential mechanisms with the protective effects of exercise is lacking. Our lab has recently published a study demonstrating that irisin, a molecule produced by muscle cells upon exercise, could be one of the molecules responsible for this effect. We have shown that irisin causes cancer cells to die with doses of chemotherapy 90 times lower than without irisin. Irisin did not change the chemotherapy sensitivity non-cancer cells. We performed a study to determine the molecular mechanisms that irisin could be using to sensitize the cancer cells to chemotherapy. Our study provided evidence that irisin was acting through a mechanism that is being intensively explored as a promising therapeutic strategy. The mechanism is called synthetic lethality. The concept of synthetic lethality refers to a pair of genes. If only one of this pair is inhibited, the cell continues to live. However, if both are inhibited, the cell dies. Therefore, drugs that inhibit synthetic lethal partners of the most common cancer gene mutations result in cell death only in cancer cells, since normal cells do not have these mutations. Interestingly, our study showed that irisin was inhibiting not only 1, but over 10 of the synthetic lethal partners of the most common cancer mutation, p53. Based on these data, we hypothesize that irisin will specifically sensitize only cancer cells with this type of mutation to chemotherapeutics. Our data suggest that combining irisin with chemotherapeutics has the potential to overcome the challenge of toxicity by lowering therapeutic doses of DNA-damaging chemotherapeutics. We also propose that this strategy has the potential to overcome the challenge of drug resistance. Previous therapeutic approaches have shown that when a single molecule is targeted, inevitably cancer cells will evolve to grow without the target, resulting in drug resistance. Because irisin targets at least 10 of the most promising p53 synthetic lethal targets, the chances of the cells evolving resistance is reduced. We propose to address the overarching challenge by developing a chemotherapy/irisin combination therapy to achieve a significantly lower dosage of chemotherapy. In order to move towards this goal, several questions must be addressed. First, the hypothesis that irisin is synthetic lethal in cancers with p53 mutation must be further investigated in multiple cell types with and without p53 mutations. Additionally, it is necessary to identify the role of the p53 synthetic lethal gene partners in the sensitization effect. Finally, it is necessary to determine the feasibility of this combination therapy in a mouse model of breast cancer. The objective of the proposed study is to address these key questions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710410
Entities
People
- Kristina Trujillo
Organizations
- United States Army
- University of New Mexico