Saposin C promotes survival and prevents apoptosis via PI3K/Akt-dependent pathway in prostate cancer cells.

Abstract

BACKGROUND:

In addition to androgens, growth factors are also implicated in the development and neoplastic growth of the prostate gland. Prosaposin is a potent neurotrophic molecule. Homozygous inactivation of prosaposin in mice has led to the development of a number of abnormalities in the male reproductive system, including atrophy of the prostate gland and inactivation of mitogen-activated protein kinase (MAPK) and Akt in prostate epithelial cells. We have recently reported that prosaposin is expressed at a higher level by androgen-independent (AI) prostate cancer cells as compared to androgen-sensitive prostate cancer cells or normal prostate epithelial and stromal cells. In addition, we have demonstrated that a synthetic peptide (prosaptide TX14A), derived from the trophic sequence of the saposin C domain of prosaposin, stimulated cell proliferation, migration and invasion and activated the MAPK signaling pathway in prostate cancer cells. The biological significances of saposin C and prosaposin in prostate cancer are not known.

RESULTS:

Here, we report that saposin C, in a cell type-specific and dose-dependent manner, acts as a survival factor, activates the Akt-signaling pathway, down-modulates caspase-3, -7, and -9 expression and/or activity, and decreases the cleaved nuclear substrate of caspase-3 in prostate cancer cells under serum-starvation stress. In addition, prosaptide TX14A, saposin C, or prosaposin decreased the growth-inhibitory effect, caspase-3/7 activity, and apoptotic cell death induced by etoposide. We also discovered that saposin C activates the p42/44 MAP kinase pathway in a pertussis toxin-sensitive and phosphatidylinositol 3-kinase (PI3K) /Akt-dependent manner in prostate cancer cells. Our data also show that the anti-apoptotic activity of saposin C is at least partially mediated via PI3K/Akt signaling pathway.

CONCLUSION:

We postulate that as a mitogenic, survival, and anti-apoptotic factor for prostate cancer cells, saposin C or prosaposin may contribute to prostate carcinogenesis at its early androgen-dependent or metastatic AI state.

• Authors: Tae-Jin Lee, Oliver Sartor, Ronald B Luftig, Shahriar Koochekpour
• Journal: Molecular cancer (Mol Cancer) Vol. 3 Pg. 31 (Nov 17 2004) ISSN: 1476-4598 [Electronic] England
• PMID: 15548330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromones
• Culture Media, Serum-Free
• Morpholines
• Neoplasm Proteins
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins
• Saposins
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Etoposide
• Poly(ADP-ribose) Polymerases
• Pertussis Toxin
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• Caspases

Topics

• Apoptosis (drug effects, physiology)
• Caspases (genetics)
• Cell Line, Tumor
• Cell Survival (genetics)
• Chromones (pharmacology)
• Culture Media, Serum-Free
• Enzyme Activation (physiology)
• Etoposide (antagonists & inhibitors, pharmacology)
• Gene Expression Regulation, Enzymologic (physiology)
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• Morpholines (pharmacology)
• Neoplasm Proteins (physiology)
• Pertussis Toxin (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Prostatic Neoplasms (enzymology, genetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt
• Saposins (physiology)
• Signal Transduction (drug effects, physiology)