Multifunctionality of Prostatic Acid Phosphatase in Prostate Cancer Pathogenesis

The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomic tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum, magnifying normally difficult to detect subsets of the protein of interest. For PAcP this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP can also occur with the wild-type PAcP signal sequence. Clinical specimens from patients with prostate cancer demonstrate that one form, termed PLPAcP, correlates with early prostate cancer. These findings confirm the analytical power of this method, implicate PLPAcP in prostate cancer pathogenesis, and suggest novel anticancer therapeutic strategies.

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Evaluation of Prostatic Acid Phosphatase (PAP) as a Candidate Antigen for the Development of Cancer Vaccines for Prostate Cancer

10.21236/ada392313 ◽

2000 ◽

Author(s):

Douglas G. McNeel

Keyword(s):

Prostate Cancer ◽

Acid Phosphatase ◽

Cancer Vaccines ◽

Prostatic Acid Phosphatase ◽

Candidate Antigen

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Prostatic Acid Phosphatase Plays a Causal Role in Prostate Cancer Bone Metastases

10.21236/ada582286 ◽

2013 ◽

Author(s):

Alice C. Levine

Keyword(s):

Prostate Cancer ◽

Acid Phosphatase ◽

Bone Metastases ◽

Prostatic Acid Phosphatase ◽

Causal Role

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Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases

Endocrinology ◽

10.1210/en.2016-1606 ◽

2016 ◽

Vol 157 (12) ◽

pp. 4526-4533 ◽

Cited By ~ 9

Author(s):

Alexander Kirschenbaum ◽

Sudeh Izadmehr ◽

Shen Yao ◽

Kieley L. O’Connor-Chapman ◽

Alan Huang ◽

...

Keyword(s):

Prostate Cancer ◽

Acid Phosphatase ◽

Bone Metastases ◽

Cross Talk ◽

Bone Cells ◽

Bone Mineralization ◽

Critical Role ◽

Prostatic Acid Phosphatase ◽

Bone Lesions ◽

Rankl Expression

Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the receptor activator of nuclear factor κ-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Coculture of PCa cells with MC3T3 preosteoblasts also revealed a role for secretory PAP in OB-PCa cross talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCa cells in OB bone metastases increases OPG and plays a critical role in the vicious cross talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa OB bone lesions.

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