Regulatory Mechanism of Noncanonical Hedgehog Signaling and Its Association with Autophagy in Castration-Resistant Prostate Cancer
Abstract
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men in the United States. Prostate cancer accounts for approximately 164,690 of all newly diagnosed cancers, of which 29,430 of men died due to this malignancy (CA CANCER J CLIN 2018; 68:7–30). Hormone manipulation, i.e. androgen-deprivation therapy (ADT) is being commonly used to treat advanced PCa. Although ADT responds well in the initial stage, most of the patients recur after a short time, and 30% of PCa patients ultimately progress to lethal castration-resistant prostate cancer (CRPC) phenotype. In addition, PCa is monitored and managed by prostate-specific antigen (PSA) screening combined with the digital rectal examination and histopathological evaluation of prostate needle biopsies. Unfortunately, neither hormonal therapy nor PSA level showed substantial benefits toward cure of PCa, which eventually progressed into CRPC; therefore, there is an urgent need to understand the precise molecular mechanisms involved in the development and progression of CRPC. Hypothesis: Several lines of evidence suggested that significant importance of the hedgehog (Hh) signaling pathway in PCa by using Hh/Gli inhibitor such as cyclopamine or anti-Shh antibodies and showed an inhibitory effect on the growth and survival of PCa in vitro and in vivo. Additionally, the crosstalk between Hh and AR signaling pathways has also been evident where Hh /Gli axis supports androgen signaling in androgen-deprived or androgen-independent prostate cancer cells. In addition, the ablation of androgen receptor signaling stimulates autophagy activity that facilitates a suitable environment for the development of CRPC. However, the regulatory molecular mechanism(s) of Hh signaling in the progression of CRPC is elusive. Based on current information, we hypothesize that Gsk3ß -mediated non-canonical mechanism of Hh signaling in the regulation of autophagy stimulation plays a vital role in the development and progression of the androgen-independent/-resistant environment of CRPC. We propose the following two specific aims to test our hypothesis: (1) to decipher the functional involvement of Gsk3ß-mediated non-canonical Hh signaling activation in CRPC and (2) to investigate the cross-association between Gsk3ß/Gli cascade and autophagy, along with its involvement in androgen-deprived and androgen-independent prostate cancer. We believe that finding from the proposed study will help us identify novel molecular targets and develop therapies to combat the progression of CRPC. Principal Investigator’s (PI’s) Career Goals: The ongoing challenges in prostate cancer research are appropriate risk stratification, diagnosis and prognosis of aggressive versus nonaggressive PCa, and understanding the biology of advanced CRPC to identify molecular targets and develop new treatment options. Considering all of these challenges, the strategic step is to study the precise molecular mechanism implicated in the etiology and pathogenesis of CRPC development and progression. Altogether, the PI intends to take advantage of this opportunity to establish her as an independent investigator in prostate cancer research. The outcomes of the study will make a contribution to the fight against prostate cancer in the future by exploring the biology of lethal CRPC to reduce death as well as permit me to acquire theoretical and practical knowledge necessary to design experiments and answer the queries related to my area of research. Applicability of the Research: My training and research work plan proposes to better comprehend the molecular signaling mechanism(s) alteration in CRPC development and progression. The proposed studies will help in better understanding of the molecular mechanisms involved in the development and progression of CRPC and will also help develop future strategies for the management and cure of CRPC patients. This study will help
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110340
Entities
People
- Jyoti Kaushal
Organizations
- United States Army
- University of Nebraska Medical Center