Cholesterol Promotes Reprogramming of Prostate Cancer Progression and Metastasis
Abstract
Background: Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in American men. Advanced prostate cancer leads to metastasis, and bone metastasis is the predominant cause of death in these patients. There are currently no effective treatments in the setting of metastatic disease. Cholesterol is known to be implicated in prostate cancer progression and pathogenesis. Cholesterol synthesis and uptake are tightly regulated in normal cells, but are dysregulated in prostate cancer cells. High cholesterol levels are identified in prostate cancer bone metastases, and hypercholesterolemia has been suggested to be associated with development of castration-resistant prostate cancer after androgen deprivation therapy in patients with bone metastasis. In line with clinical findings, our preclinical data demonstrate that high cholesterol diets promoted and enhanced prostate cancer bone and soft tissue metastases in mice, including increased numbers of disseminated tumor cells (DTCs). When isolated from mouse bone marrow, these DTCs expressed elevated levels of biomarkers of aggressive disease. Furthermore, we discovered that exogenously delivered cholesterol transformed and reprogrammed prostate cancer cells to undergo a mesenchymal transition via activation of Gli1 and FOXM1, key transcription regulators that are known to drive aggressive prostate cancer. Expression of these two factors correlates with increased risk of clinical progression. Moreover, cholesterol-activated Gli1-FOXM1 signaling increased the levels of Shh and RANKL produced by the cancer cells, creating an autocrine feed-forward signaling pathway that promotes interactions between tumors and the surrounding stromal cells in the bone microenvironment. This enhanced tumor-stroma interaction subsequently results in increased bone remodeling, thereby facilitating prostate cancer bone colonization. We demonstrated further that targeting intratumoral cholesterol by a novel tumor-specific cholesterol-lowering agent not only significantly decreased Gli1-FOXM1 expression, but also attenuated AR expression and signaling and effectively inhibited the growth of prostate cancer cells in both cell and animal models. This finding supports the clinical observation that lowering cholesterol in patients is associated with delayed prostate cancer progression and reduced risk of recurrence and mortality, thereby reducing the incidence of lethal progression to bone. Together, targeting intratumoral cholesterol and blocking Gli1-FOXM1 signaling and downstream effectors could serve as a proof-of-concept study that will address how cholesterol promotes prostate cancer progression and metastasis and lead to potential development of more effective and targeted treatments for metastatic prostate cancer. Objective and Aims: The objective of this proposal is to investigate how cholesterol reprograms prostate cancer cells and whether increased expression and activation of Gli1 and FOXM1 signaling is the underlying molecular basis for cholesterol-enhanced prostate cancer bone and visceral metastases. The proposed Aim 1 is to understand the mechanisms by which cholesterol reprograms prostate cancer cells via enhanced Gli1-FOXM1 signaling and promotes tumor-stroma interactions mediated by Shh/RANKL paracrine signaling in the bone microenvironment. Aim 2 is to evaluate the effectiveness of targeting intratumoral cholesterol, using a novel tumor-specific cholesterol-lowering agent, on the “deprogramming” of prostate cancer cells and disengaging of tumor-stroma interactions, thereby abrogating PC metastasis. Clinical Relevance: The proposed study will benefit prostate cancer patients at all stages of disease progression, particularly late-stage patients with metastatic and castration-resistant prostate cancer. We propose to use a double-pronged strategy to treat metastatic prostate cancer by: (1) targeting cholesterol-activ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810252
Entities
People
- Chia-yi Chu
Organizations
- Cedars-Sinai Medical Center
- United States Army