Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer

Abstract

Advanced prostate cancer (CaP) is often treated with androgen deprivation therapy (ADT). Despite high initial success rates of this therapy, recurrence of the cancer in a castration-resistant (CRPC) form is inevitable. It has been demonstrated that, despite the low levels of circulating androgens resulting from ADT, intratumoral androgen levels remain high and androgen receptor activation persists. Recently, it was discovered that de novo androgen synthesis is occurring within the tumor cells themselves, thus providing a potential mechanism for the high endogenous concentrations. A common upstream precursor in this steroidogenic pathway is cholesterol. For many decades, the breakdown of cholesterol homeostasis in cancer has been the focus of research, but this was largely to elucidate its involvement in maintaining membrane integrity and cell signaling. De novo steroidogenesis has provided a new avenue for cholesterol research and reinforces the importance of understanding the mechanisms that lead to the alterations in cholesterol regulation in the progression to CRPC. The findings to date suggest that cholesterol homeostasis is altered to support de novo androgen synthesis and appear to facilitate disease progression. We further propose that a better understanding of the link between cholesterol and de novo androgen synthesis in CaP progression may provide opportunities for novel therapeutic intervention, namely via eliminating sources of the precursor cholesterol. This review summarizes the implications of cholesterol dysregulation in CaP and particularly in the post-ADT castration-resistant state, as well as the potential implementation of novel therapies targeting these cholesterol sources.

Androgen deprivation of prostate cancer: Leading to a therapeutic dead end

“…This may be caused by an enhanced gene expression of numerous enzymes mediating intracellular androgen metabolism from adrenal dehydroepiandrosterone (DHEA) or androstenedione to testosterone and dihydrotestosterone (DHT) [34,35]. Furthermore, proteins involved in cholesterol homeostasis are altered in androgenindependent growing tumor cells in a manner that appears to be generating free cholesterol that may be used to provide precursor to the steroidogenic pathway [36].…”

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…mechanisms continue to be defined (Swinnen et al, 2006;Di Vizio et al, 2008;Patra, 2008;Batarseh and Papadopoulos, 2010;Twiddy et al, 2010). Important growth-signaling complexes for pathways such as TGFb, EGFR/MAPK/ERK, AKT, and the AR reside within cholesterol-rich microdomains referred to as lipid rafts whose signaling integrity can be modulated by changes in cellular cholesterol levels that affect membrane fluidity, transport, and protein complex assembly and stability Freeman et al, 2007;Montero et al, 2008).…”

“…A role for elevated cholesterol has been implicated in the etiology and disease progression in prostate and breast cancer, with emphasis on its role as a precursor to steroid metabolism and intracrine growth mechanisms (Di Vizio et al, 2008;Twiddy et al, 2010). However, there is also a separate recognition that elevated intracellular cholesterol in non-hormone-dependent tumor cells can contribute to progression based on numerous reports of interference with multiple pathways of growth signaling and apoptosis (Zhuang et al, 2005;Li et al, 2006;Swinnen et al, 2006;Adam et al, 2007;Freeman et al, 2007;Martinez-Abundis et al, 2007;Oh et al, 2007;Christenson et al, 2008;Patra, 2008).…”

GnRH agonists and the rapidly increasing use of combined androgen blockade in prostate cancer

“…A suggested source of testosterone in CRPC is cholesterol (Twiddy et al 2011). LNCaP cells have been reported to be able to transform radiolabeled cholesterol into testosterone in vitro and in vivo (Dillard et al 2008, Locke et al 2008, 2009).…”