Date of Award

8-2022

Document Type

Dissertation

Degree Name

Ph.D.

Department

Basic Medical Sciences

Committee Chair

Ajay Singh, Ph.D

Abstract

Tobacco or cigarette smoking is the leading cause of several diseases, including cancer, in the United States and worldwide. Epidemiological data provide strong evidence for an association of nicotine with prostate cancer risk and recurrence, but experimental data is largely lacking. Nicotine is an addictive ingredient of tobacco products and other alternatives, however, its role in prostate tumor biology has not been explored. Further, while a role of smoking in immunosuppression has been demonstrated, the effect of nicotine on immune function is largely unknown. We hypothesized that nicotine suppresses immune function by promoting alternative polarization of macrophages and promotes prostate cancer cell growth, malignant behavior and therapy-resistance by activating tumor-supportive signaling mechanisms. Macrophages are an important component of the innate immune system having both pro-and anti-inflammatory functions depending upon their polarization state. M1 polarized macrophages have pro-inflammatory functions, while M2 polarized macrophages play a role in tissue repair and resolution of the inflammatory response. Most prostate tumors rely on androgen receptor (AR) signaling and aberrant activation of AR signaling is considered a major mechanism underlying the failure of primary androgen-deprivation therapy (ADT) or resistance to AR signaling inhibitors, such as enzalutamide. Our studies demonstrate that nicotine induces M2 polarization of macrophages as well as promotes their growth, migration, and invasion. Mechanistic investigations xiii demonstrate a role Src-mediated phosphorylation of STAT3 in nicotine-induced polarization, proliferation, and motility of macrophages. Moreover, we observe that nicotine treatment augments the growth and malignant behavior of prostate cancer cells and promotes resistance to androgen-depletion and enzalutamide treatment. We also observe that nicotine exposure increases the expression of MYB, a transcription factor protein involved in prostate cancer pathogenesis and therapy resistance, and AR-V7, a constitutively active AR splice variant. We also show that nicotine sustains the transcriptional activity of AR in absence of androgens and promotes phosphorylation of numerous signaling proteins of pathogenic significance. In addition, we demonstrate that nicotine induces AR-V7 expression via alpha7-nAChR-mediated activation of Src and AKT. Overall, our findings suggest a significant role of nicotine in immunosuppression and prostate cancer pathogenesis and should serve as a foundation for future studies to further explore its multifaceted roles in prostate carcinogenesis, tumor-stromal crosstalk, and immune biology.

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