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


CONCLUSIONS
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.
Lee
Tae-Jin
TJ
Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, 533 Bolivar Street, CSRB 4-17, New Orleans, LA 70112, USA. tlee@lsuhs.edu <tlee@lsuhs.edu>
Sartor
Oliver
O
Luftig
Ronald B
RB
Koochekpour
Shahriar
S
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation / Q000502:physiology; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D049231:Saposins / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D020169:Caspases; D002867:Chromones; D016895:Culture Media, Serum-Free; D005047:Etoposide; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D009363:Neoplasm Proteins; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D049231:Saposins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human