Shahriar Koochekpour, MD, PhD

We have focused our laboratory investigation on the following two major topics:

A) Determine the biological significance of PROSAPOSIN expression and function in prostate cancer invasion and metastasis

Prosaposin (PSAP): The human polycistronic PSAP gene spans 20 kb on chromosome 10q22.1 and consists of 15 exons. It encodes a 65-72 KDa polypeptide containing a signal peptide and four highly conserved saposin domains that exist in tandem. The full-length precursor molecule contains complex oligosaccharide chains that are probably the result of cotranslational glycosylation of the 53-kDa polypeptide core. After processing through the Golgi complex (GC), the newly synthesized PSAP enters the lysosome; where it is cleaved into four mature saposins (8-13 kDa), that are required for intracellular degradation of ceramide (Cer) and certain sphingolipids (Fig. 1). Saposins are highly homologous molecules, each with approximately 80 amino acids containing 6 cysteine residues and N-glycosylated carbohydrate chains that are highly conserved.


Fig. 1: Structure of the prosaposin protein organization. A) Saposin domains and signal peptide (cross-hatched) are indicated; white blocks represent the intersaposin amino acid sequences that are proteolytically cleaved during the processing to mature saposins; glycosylation sites and exon-intron boundaries are shown by arrow symbols and vertical lines, respectively. B) Saposin C amino acids sequence; TX14A contains a 12-mer sequence encompassing the hydrophilic region of saposin C.

PSAP and saposins also exist as extracellular soluble proteins found in culture supernatant, serum, and prostatic secretions. PSAP expression in normal cells is at either very low or undetectable levels. The secreted form of PSAP is a well-known neurotrophic factor involved in the growth, development, and maintenance of the nervous system. However, its expression and biological significance in cancer or specifically in PCa remain largely unknown. The neurotrophic activity of PSAP has been attributed to the NH₂-terminal sequence of the saposin C domain (Fig. 1), which is the only domain that mimics all biological activities of PSAP. Homozygous inactivation of PSAP gene leads to distinct abnormalities in the male reproductive organs, with gross pathological features including a reduction in size and weight of the testes, seminal vesicles, and prostate gland. Histological examination of the involuted prostate tissue shows the presence of undifferentiated epithelial cells. These data support a role for PSAP in prostate development.

My laboratory is investigating the role of PSAP in prostate carcinogenesis and its progression toward androgen-independent or advanced metastatic state.

So far, we have discovered that:

1) PSAP is exclusively overexpressed in androgen-independent prostate cancer cells.

2) PSAP is genomically amplified in the metastatic androgen-independent prostate cancer cell lines (PC-3, DU-145, MDA-PCa 2b, M-12, and NCI-H660), LuCaP-58 and -96 xenografts and in punch biopsy samples of lymph node metastases.

3) PSAP or its neurotrophic domain (saposin C) stimulates prostate cancer cells migration and invasion, activates several interacting signal transduction pathways (e.g., PI3K/Akt, p42/44 MAPK, p38 MAPK).

4) PSAP not only regulates AR/PSA expression and activity, but also is an androgen-regulated gene.

B) Define the biological significance of ANDROGEN RECEPTOR and PROSAPOSIN expression and signaling in prostate cancer invasion and metastasis in AFRICAN AMERICANS.

According to the SEER database, African American (AA) men have 1.6-1.9 times higher incidence rate for invasive prostate cancer and 2-3.1 times greater mortality rate than Caucasian Americans (CAs). AA men with prostate cancer present with higher tumor volume, more advanced tumor stage, higher Gleason grade, and higher prostate specific antigen (PSA). Overall, AA men have a worse prognosis than their Caucasian counterparts. The underlying reasons for such disproportionate ethnic differences in prostate cancer prognosis and mortality may reflect genuine racial differences in cancer biology, socio-cultural differences and/or access to health care systems. Currently, the unequivocally identified risk factors for prostate cancer are ethnic origin and a familial history of the disease. Familial types of prostate cancer with at least two first-degree relatives affected account for 20% of cases and hereditary transmission compatible with Mendellian inheritance, accounts for 50%. Most other familial forms and sporadic cases involve genetic factors, but in a polygenic or multifactorial mode of inheritance. In younger patients, the proportion of genetic susceptibility is larger. For example, 34% and 43% of prostate cancer is diagnosed at 70 and 55 years of age, respectively. Clinical and histopathological data suggest that, there is a dormant form of prostate cancer without evolution that is not associated with mesologic or ethno-geographic variations, suggesting that there are various levels of genetic regulation, some associated with the initial carcinogenesis phase and some with the progression phase.

Our objectives are to:

-Determine the incidence of somatic and germline mutations in androgen receptor (AR) in African Americans with sporadic or familial prostate cancer

-Define the role of AR heterogeneity in prostate cancer initiation, progression, and response to therapy in African Americans

- Determine the underlying mechanism(s) for PSAP regulation of AR in invasive and metastatic behavior of prostate cancer in African Americans.