Cigarette smoking is responsible for 85 percent of all lung cancers in the United States, which is the most common cause of cancer death, responsible for an estimated 160,000 deaths in the United States annually. Conventional therapies of surgery, radiotherapy, and chemotherapy for improving morbidity, mortality, and quality of life of lung cancer are not likely. Cancer prevention remains the ideal strategy for reducing the incidence of lung cancer, as a majority of lung cancer cases are due to environmental, dietary, or lifestyle factors, which are avoidable. Epidemiological, ecological, animal and in vitro studies have demonstrated that dietary compounds or diet modifications may ultimately play a major role in the reduction of occurrence of lung cancer. Consumption of docosahexacnoic acid (DHA), an omega-3 fatty acid rich in fish oil, prevents tumor growth and development. Supplementing the diet with omega-3 fatty acids may be a nontoxic means to slow or prevent lung cancer growth and to improve cancer treatment outcomes. However, the intracellular protein factors mediating its beneficial effects remain to be identified and studied, which has hampered our rational dietary modifications for lung cancer prevention and therapy.
DHA binds to a protein factor called RXR-alpha. However, whether and how RXR-alpha protein functions to mediate the cancer preventive effect of DHA is unknown. Recent scientific progress demonstrate that RXR-alpha possesses two unexpected functions, migration to mitochondria in cells to eliminate cancer cells by a death process called apoptosis and inhibition of the activities of a protein called beta-catenin that functions to promote cancer growth and metastasis. In my preliminary study, I found that DHA could influence the cellular localization of RXR-alpha in cancer cells. More interestingly, altered RXR-alpha cellular localization in response to DHA treatment resulted in apoptosis and degradation of beta-catenin. My observations suggest that DHA may exert its anti-cancer effects by altering RXR-alpha subcellular localization, resulting in degradation of beta-catenin and cancer cell death. Based on these results, I hypothesize that RXR-alpha is an important intracellular protein factor mediating the anticancer effects of dietary DHA. In the proposed research, I plan to determine whether DHA inhibits cancer cell growth by binding to RXR-alpha. My goal will be accomplished by four specific studies: 1). To study whether RXR-alpha protein is required for the anti-cancer effects of DHA by studying whether reducing RXR-alpha protein levels by siRNA approach will diminish the anti-cancer effects of DHA; 2). To determine whether DHA modulates the cellular localization of RXR-alpha protein in lung caner cells and whether altered RXR-alphacellular localization attributes to the anti-cancer effects of DHA; 3). To study whether DHA induces degradation of beta-catenin protein requires its binding to RXR-alpha protein and is mediated through a process called ubiquitination; and 4). To analyze whether DHA sensitizes the apoptotic effect of chemotherapeutic agents by inducing a migration of RXR-alpha protein and its partner death protein called Nur77 to mitochondria.
This application addresses the public’s interest regarding solid scientific basis governing the beneficial effect of dietary DHA, so that appropriate nutrition modifications and dietary supplements can be used for lung cancer prevention. In addition, results from these studies may offer a new strategy to enhance the efficacy of chemotherapeutic agents by dietary modifications. |