GROUP LEADER: Dr Karl Storbeck
Position: Senior lecturer
Office: A116 JC Smuts Building
PhD, University of Stellenbosch, Biochemistry, 2008
Castration resistant prostate cancer, Steroid hormones, Adrenal androgens, Cytochromes P450, Hydroxysteroid dehydrogenases, Cytochrome b5
Steroid hormones play a vital role in the regulation of metabolism, inflammation, immune function, salt and water balance, stress management, and reproduction in all mammals. While these hormones are essential to normal physiological function, they also contribute to the pathogenesis of a number of disease states, such as hormone dependent cancers. Our research focuses on the production of steroid hormones by steroidogenic tissue, the down-stream metabolism of these hormones in peripheral tissue and the role that this metabolism plays in health and disease states.
The role of the adrenal steroid 11β-hydroxyandrostenedione (11OHA4) in castration resistant prostate cancer (CRPC)
Androgens (male sex hormones) are vital for the development and differentiation of the healthy prostate. Almost all prostate cancers are dependent on circulating androgens for progression. The primary androgen in healthy males is testosterone, which is produced by the testes. In target tissue, such as the prostate, testosterone is reduced by the enzyme steroid 5α-reductase (SRD5A) to form 5α-dihydrotestosterone (DHT), the most potent androgen. Current treatment of androgen dependent prostate cancer relies on androgen deprivation therapy by either surgical or chemical castration. While androgen deprivation initially demonstrates a dramatic response, in most cases the improvement is transient with the cancer progressing to castration resistant prostate cancer (CRPC). CRPC cells are able to metabolise the C19 adrenal steroids DHEA(S) and androstenedione (A4) to DHT, while bypassing testosterone completely. Our group has shown that the adrenal steroid 11β-hydroxyandrostenedione (11OHA4), which previously had no known function, is metabolised to novel androgens (11OHDHT and 11KDHT) in prostate cancer cells, thereby implicating this orphan steroid as a role player in CRPC. We are currently characterising the 11OHA4 pathway and investigating its role in driving CRPC.
The identification of novel biomarkers for prostate cancer
Prostate cancer is the second most common cancer in the world. Prostate-Specific Antigen (PSA) is currently the only biological marker (biomarker) routinely used to test for this disease. Increased PSA levels are, however, not unique to prostate cancer and also occur as a result of a number of benign conditions, including prostatitis and benign prostatic hyperplasia. As a result only about 30 percent of men who have a prostate biopsy due to an elevated PSA level are diagnosed with prostate cancer. The use of PSA as a routine test for prostate cancer has therefore been brought into question. We are currently employing Mass Spectrometry-based proteomic technologies to investigate the secretomes (the proteins secreted from a cell) of a number of different prostate cell models with the aim of identifying potential biomarkers for prostate cancer and the castration resistant condition.
Cytochrome b5 is a small membrane bound hemoprotein associated with cytochrome P450 function. During steroidogenesis cytochrome b5 selectively allosterically augments the 17,20-lyase activity of cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) without affecting the hydroxylase activity catalysed by the same enzyme. We have also recently demonstrated that cytochrome b5 can allosterically augment the activity of 3β-hydroxysteroid dehydrogenase (3βHSD) by increasing the enzymes affinity for its cofactor NAD+. During steroidogenesis CYP17A1 and 3βHSD compete for the same steroid substrates, the influence of cytochrome b5 can therefore alter the output of the steroidogenic pathway. We have shown that cytochrome b5 forms homomeric complexes in vivo and that these complexes may be inactive, while monomeric cytochrome b5 is active. We are therefore investigating if homomeric complex formation by cytochrome b5 is a mechanism by which steroidogenesis can be regulated.
A broad range of techniques are used to study the steroid hormones and the enzymes responsible for their metabolism. These include molecular biology, tissue culture, protein expression and purification, enzymatic assays and UPLC-MS/MS.
Please see https://www.researchgate.net/profile/Karl-Heinz_Storbeck/ for a list of publications