koochekpour_shahriar

Shahriar, Koochekpour, MD PhD

Assistant Professor of Urology

Assistant Professor of Urology

School of Medicine
Louisiana State University Health Sciences Center
533 Bolivar Street, CSRB 4-17
New Orleans, LA 70112

Phone:  (504) 568-7261  (office)    

             (504) 568-4382  (laboratories) - or -
             (504) 568-2021

    Fax:  (504) 568-6888

Degrees

MD - 1990
Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran

PhD Experimental Cellular and Molecular Oncology - 1995
Kings College School of Medicine, University of London, London, U.K

Bio

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.

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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.

Recently, we demonstrated that, in metastatic PCa cells, stable down-modulation of PSAP by RNA-interference via a lysosomal proteolysis-dependent pathway decreased beta1A-integrin expression, its cell-surface clustering, and adhesion to basement membrane proteins; led to disassembly of focal adhesion complex; and decreased phosphorylative activity of focal adhesion kinase and its downstream adaptor molecule, paxillin. Cathepsin D (CathD) expression and proteolytic activity, migration, and invasion were also significantly decreased in PSAP knock-down cells. Transient-transfection studies with beta1A integrin- or CathD-siRNA oligos confirmed the cause and effect relationship between PSAP and CathD or PSAP and Cer-beta1A integrin, regulating PCa cell migration and invasion. Our findings suggest that by a coordinated regulation of Cer levels, CathD and beta1A-integrin expression, and attenuation of "inside-out" integrin-signaling pathway, PSAP is involved in PCa invasion and therefore might be used as a molecular target for PCa therapy.



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.

Research Interests

Prostate cancer biomarkers

Clinicohistopathological significance of PSAP in prostate carcinogenesis and its androgen-independent or metastatic progression

AR-dependent signaling and androgen-independent progression of prostate cancer

Gene-specific and global-methylation and metastatic progression of prostate cancer

Defining the sensitivity of microsatellites instability as prostate cancer biomarkers

Teaching Activities

       Ray J. Scioneaux, B.Sc         D. Subramani, B.Sc

ray_scioneaux d_subramani

       S. Majumdar, PhD                   B. Wood, B.Sc

s_majumdar b_wood

      Eric Buckles, PhD                    Mohamed E. Abdraboh, PhD

Eric Buckles 2011 9:20:25 AM

Selected Publications

Koochekpour, S, Zhuang, Yu-Jun, Beroukhim, R, Hssieh C-L, Hofer, M. D, Zhau, HE,Hiraiwa, M, Pattan, D, Ware, J. L, Luftig, R, Sandhoff, K, Sawyers, C. L, Pienta K.J, Rubin MA, Vessella RL, Sellers WR, and Sartor, O. Amplification and Overexpression of Prosaposin in Prostate Cancer and Other Malignant Cells. Genes, Chromosomes & Cancer, 44, 351-364, 2005.

Koochekpour S. PSAP (Prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)). Atlas Genet Cytogenet Oncol Haematol, 10: 370-384, 2006.

URL:http://www.infobiogen.fr/services/chromcancer/Genes/PSAPID42980ch10q22.html, Review Article.

Koochekpour, S., Lee, T-J., Wang, R., Sun, Y., Delorme, N., Caffey, S., Grabowski, GA., Culig, Z., Minokadeh, A. Prosaposin is a novel androgen-target gene. J. Cell. Biochem, 2007. J Cell Biochem. 101:631-641, 2007.

Koochekpour, S., Lee, T-J., Wang, R., Vadlamudi, R. K., Zoran Culig., Delorme, N., Caffey, S., Marrero, L., Aguirre, J., Garcia, M.Z. Prosaposin Upregulates Androgen Receptor Expression and Activity In Prostate Cancer Cells (LNCaP), Prostate, 67, 178-189, 2007.

Sujit S. Nair, Mueller, J. M., Koochekpour, S., Qiu, Y., Tekmal, R. R., Schüle, R., Kung, H-J., Kumar, R., and Vadlamudi, R. K. PELP1/MNAR modulates transactivation of LIM-only coactivator FHL2. Mol. Endocrinol, 21, 613-624, 2007.

Koochekpour S, Lee TJ, Sun Y, Hu S, Grabowski GA, Liu Z, Garay J. Prosaposin is an AR-target gene and its neurotrophic domain upregulates AR expression and activity in prostate stromal cells. J Cell Biochem, 104, 2272-2285, 2008.

Singh G, Aras S, Zea AH, Koochekpour S, Aiyar A. Optimal transactivation by Epstein-Barr nuclear antigen 1 requires the UR1 and ATH1 domains. J Virol, 83, 4227-4235, 2009.

S, Hu, N, Delorme, Z, Liu,T, Liu,C, Velasco-Gonzalez, J, Garai., A, Pullikuth., and Koochekpour, S. Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion. Molecular Cancer. 9, 30, 2010. 

S. Hu, T. Liu, Z. Liu,E. Ledet, C. Velasco-Gonzalez, D. M. Mandal, S.Koochekpour.Identification of a Novel Germline Missense Mutation of the Androgen Receptor in African American Men with Familial Prostate Cancer. Asian J Andrology, 12 (3): 336-343, 2010. 

D’Antonio, J., Antony, Vander Griend, D. J., L., Dalrymple, S.L., Koochekpour, S., Isaacs, JT. Loss of growth suppression is necessary but not sufficient for prostate cancer cells acquiring  oncogen addition to androgen receptor signaling. PLoS One. 5 (7):e11475, 2010.

Koochekpour, S.Androgen receptor signaling and mutations in prostate cancer. Asian J. Andrology, Aug 16, 2010. [Epub ahead of print]. Invited Review Article.