Novel Mechanisms of Β-Adrenergic Signaling In Prostate Cancer Progression

<p>Prostate cancer is the second leading cause of cancer death among American men. The American Cancer Society estimates that 180,890 men will be will be diagnosed with prostate cancer in 2016 in the USA. (http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics). Androgen deprivation therapy (ADT) is the standard treatment for early stage prostate cancer. But most patients relapse with aggressive variants of prostate cancer, with survival time between 1-3 years. In order to develop cure for such aggressive variants of prostate cancer, our present understanding of the mechanisms underlying its progression needs to be advanced.</p> <p>Recently, it has been found that activation of β-adrenergic signaling pathway leads to aggressive variants of prostate cancer. β-adrenergic signaling involves the activation of β-adrenergic receptors (ADRBs), eventually leading to increased activation of cAMP response element-binding protein (CREB). Downstream targets of CREB activation in neuroendocrine differentiation as well as in neoangiogenesis are largely unknown, indicating that the underlying mechanisms of β-adrenergic signaling in prostate cancer progression are far from completely understood. For instance, while the epigenetic regulation by histone deacetylases 2 (HDAC2) is necessary for stress to induce cardiac hypertrophy, its mechanism are unknown in cancer progression. Similarly, another regulator of β-adrenergic signaling, GRK3 was recently shown to be a new critical regulator of prostate cancer progressionand tumor angiogenesis. However, mechanisms of GRK3 in prostate cancer progression and its regulation by ADRB2 signaling remain unknown.</p> <p>Our <strong>hypothesis</strong> is that GRK3 and HDAC2 are critical downstream effectors of β-adrenergic signaling-activated CREB in promoting prostate cancer progression. Here, we show that CREB directly activates GRK3 transcription by binding to its promoter and this up-regulation of GRK3 expression by ADRB2/CREB pathway is sufficient as well as necessary to induce the neuroendocrine differentiation of prostate cancer cells. We also show that downstream of chronic stress and ADRB2, CREB binds to HDAC2 promoter and activates its expression. HDAC2 further suppresses the expression of thrombospondin 1 (TSP1) in order to induce angiogenesis, thus acting as a mediator for the β-adrenergic signaling pathway.</p> <p>Here, we have introduced two new pathways acting downstream of the ADRB2/CREB axis. We show that the CREB/GRK3 axis leads to neuroendocrine prostate cancer progression. We have introduced a new paradigm that β-adrenergic signaling and epigenetic gene expression regulation may be working synergistically resulting in cancer progression.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2016

Author dc:creator

• Hulsurkar, Mohit

Contributors dc:contributor

• WENLIANG LI, Ph.D.
• ZHIQIANG AN, Ph.D.
• QINGYUN (JIM) LIU, Ph.D.

• Chronic Stress
• beta-adrenergic signaling
• HDAC2
• TSP1
• angiogenesis
• cancer progression
• GRK3
• CREB
• neuroendocrine prostate cancer
• Biotechnology
• Cancer Biology
• Cell Biology
• Cellular and Molecular Physiology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/699

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1743