Signaling Interplay Underlying Prostate Cancer Racial Disparity
Abstract
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy and second leading cause of cancer-related death in males in the United States. It also exhibit one of the most significant disparities in incidence and clinical outcomes. Especially, African American (AA) men are nearly at two-third higher risk of being diagnosed with PCa and two-times more likely to die because of it, compared to the Caucasian American (CA) men. Over the past several decades, we have made significant advancements in our understanding of PCa biology and therapeutic management, but a significant proportion of patients still continues to succumb to this disease, sooner or later, due to the therapy failure and disease recurrence. Androgen deprivation or castration therapy (ADT/CT) remains the mainstay for the treatment of advanced and metastatic PCa, but the tumors relapse in a castration- resistant (CR) form after an initial clinical response in most of the cases. CR PCa are highly aggressive and do not respond optimally to other alternative therapies as well, resulting in a poor prognosis. Thus, it is extremely imperative to characterize mechanisms underlying disease progression and therapy resistance, and use that knowledge to develop novel preventive and therapeutic interventions. To address race-associated PCa health disparities, it is important to first understand how tumors from different races differ in their biology and molecular landscape. In that regard, we have made several preliminary observations that provide us clues for possible mechanistic underpinning of PCa racial disparities. We have observed that AA PCa has higher expression of MYB, a protein associated with disease aggressiveness and castration therapy resistance. Interestingly, high MYB expression is also detected in androgen receptor (AR) negative prostate cancer cells and in cell lines derived after prolonged exposure to antiandrogen (enzalutamide). These cells also tend to express higher levels of glucocorticoid receptor (GR), a protein linked with emergence of enzalutamide resistance. Furthermore, we observe that AA PCa patients have higher levels of cortisol (glucocorticoid, a stress hormone) and IL6 (an inflammatory cytokine) in their serum compared to CA PCa patients. Interestingly, we also observe that IL6 induces MYB expression and MYB forms a complex with ligand activated GR in PCa cells. Moreover, glucocorticoid/dexamethasone treatment promotes PCa cell survival and enzalutamide resistance, which is dependent on MYB overexpression. These compelling findings have led us to hypothesize that enhanced expression of MYB in AA PCa mediates the crosstalk of stress (Cortisol/GR) and inflammatory (IL6/STAT3) signaling pathways to drive PCa aggressiveness and therapy resistance. We will test this hypothesis in three specific aims by (i) investigating mechanisms of IL6-mediated MYB upregulation and gene regulatory consequences of MYB-GR crosstalk in PCa cells, (ii) establishing the pathobiological significance of MYB-mediated GR and IL6 signaling crosstalk in aggressive PCa progression and therapy resistance, and (iii) examining the correlative expression of MYB, GR, and IL6 and their racial association and collective significance with the clinicopathologic progression of PCa. Resulting data from proposed innovative studies will provide experimental, mechanistic, pre-clinical and clinical support for a novel signaling interplay driving PCa aggressiveness, therapy resistance, and racial disparities. In the longer term, this information can be useful for devising novel approaches for risk prediction and PCa management leading to reduction of disparity gaps.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310452
Entities
People
- Ajay Singh
Organizations
- United States Army
- University of South Alabama