Role of TUBB4A in Racial Disparities, Tumor Metastasis, and Chemotherapy Resistance
Abstract
Rationale: In the United States, prostate cancer (PCa) is the second-leading cause of cancer-related deaths of men. In particular, African-American (AA) PCa patients have a higher mortality rate, more metastatic disease at diagnosis, and more poor outcomes due to chemotherapy resistance compared to other ethnic patients. Unfortunately, the mechanisms of these racial disparities are not fully understood. Lethal PCas can be defined as tumors that spread to other organs, such as the bones, lungs, and liver. Sometimes when doctors remove the original PCa, they later diagnose prostate tumors growing in distant areas of the body. Currently, hormone therapy is a usual first-line option for men with advanced PCa, but most eventually progress to the lethal type of PCa (e.g., metastatic, castration-resistant PCa, mCRPC). Once resistance to hormone therapy has developed, few effective treatment options remain. Although docetaxel-based chemotherapy is the first-line option for men with mCRPC and benefits survival and quality of life, acquired chemotherapy resistance is a major obstacle limiting the success of drug treatment. This shows the urgent need to identify molecular mechanisms and targets that cause this resistance, which can guide development of new drugs and clinical decision-making for patients suffering from lethal PCa, especially for AA patients. Current technologies allow us to sequence genes and thereby characterize gene alterations during tumor metastasis and development of resistance to chemotherapy. Docetaxel (DTX) is a drug that functions by binding to ß-tubulin, but high levels of ß-tubulin enhance chemotherapy resistance to DTX treatment. Recently, we observed high levels of ß4a-tubulin (TUBB4A), a member of ß-tubulin family, in PCa tumors, especially in AA PCa tumors. In AA PCa cells, this protein facilities tumor metastasis and resistance to DTX treatment. We now provide the first evidence that, in AA PCa cells, deletion of the TUBB4A gene reduces tumor metastasis and increases tumor sensitivity to DTX chemotherapy. Scientific Objective: We therefore hypothesize that the dysfunction of TUBB4A causes AA racial disparities, tumor metastasis, and chemotherapy resistance. Our goal is to define the mechanism underlying the TUBB4A-mediated AA racial disparities, tumor metastasis, and chemotherapy resistance, thereby improving existing therapeutic strategies for AA patients who are suffering from lethal PCa. In this proposed work, we will use human specimens and animal models to determine the role and mechanism of TUBB4A in AA PCas. If our hypothesis is validated, our discoveries will help doctors develop more effective diagnoses and treatment options for AA patients with PCa. In addition, TUBB4A appears to be tumor-specific in PCa tumors and not expressed in most human tissues, including prostate tissue. Thus, TUBB4A is a potential biomarker for AA PCas and a promising target for PCa treatment. Also, targeting of TUBB4A should inhibit tumor metastasis and overcome chemotherapy resistance, with few side effects to normal tissues in AA patients with PCa. Ultimate Applicability of the Research: In future clinical applications, our results will help in understanding lethal AA PCas, and they have the potential to develop new biomarkers for predicting tumor metastasis and resistance as well as new-targeted therapies for AA patients with drug-resistant, lethal PCas. How Is This study Relevant to One or More of the FY20 PCRP Health Disparity Research Award Focus Areas? “Biological contributors” What Are the Likely Contributions of this Study Toward the FY20 PCRP Overarching Challenges? Our goal is to identify biological factors associated with lethal AA PCas, meeting the three Overarching Challenges to (1) reduce lethal prostate cancer in people of African descent, (2) define the biology of lethal prostate cancer to reduce death, and (3) develop treatments that improve outcomes for men wit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110100
Entities
People
- Lizhong Wang
Organizations
- United States Army
- University of Alabama at Birmingham