Steroidogenesis, the biological process by which the body generates steroid hormones, facilitates the production of androgens, the male sex hormones, from cholesterol. While androgen levels influence normal biological functions, they can also play a role in diseases, including prostate cancer.
Prostate cancer cells require testosterone, an androgen responsible for many male characteristics, like facial hair and muscle strength, to grow. Some evidence supports the role of testosterone in early prostate cancer development. Because a healthy prostate does not make testosterone itself, prostate cancer cells rely on testosterone synthesis occurring in specialized cells called Leydig cells, located in the testes.
The requirement of testosterone for prostate cancer growth has led to the use of hormone therapies, prostate cancer treatments that decrease androgen levels or block their function. While highly effective initially, most patients will stop responding to these therapies in what becomes classified as castrate-resistant prostate cancer (CRPC). In these cases, testosterone levels continue to rise. However, until now, the source of testosterone remained unknown.
A recent study in Nature Communications demonstrates how prostate cancer cells sense the testosterone draught and generate their own cholesterol for steroidogenesis. The study uncovers a prominent role for a protein called sterol regulatory element-binding protein 1 (SREBF1) which can sense when androgen levels diminish. Upon sensing androgen deficiency, SREBF1 separates from the androgen receptor and moves into the nucleus, where it undergoes epigenetic changes resulting in cholesterol overproduction, prompting steroidogenesis.
SREBF1 levels in the nucleus increase in patients with late-stage prostate cancer. However, the study shows that blocking the nuclear translocation and epigenetic changes using a dual inhibitor combination of CPTH2 and Afatinib, a drug approved for treating some lung cancers. This combination therapy effectively slowed the growth of prostate tumors in mouse models. To support this improved tumor control, treated mice had higher numbers of T cells, the immune cells required for anti-tumor immunity. Further, the T cells in treated mice expressed fewer markers that indicate cell exhaustion and inability to carry out anti-tumor responses.
The study concluded that prostate cancer cells, in contrast to healthy prostate cells, elicit a workaround to generate testosterone to fuel their own growth. This allows the cancer to grow, even without testes-driven testosterone production. Blockade of cellular modification events enables prostate cancer cells to circumvent the normal steroidogenesis pathways, and further investigation of such approaches may provide a new avenue for therapeutic development.
Sources: Endocr Rev, NLM, Ther Adv Urol, Nature Communications, J Med Chem