A Synthetic 15-mer Peptide (PCK3145) Derived from Prostate Secretory Protein Can Reduce Tumor Growth, Experimental Skeletal Metastases, and Malignancy-Associated Hypercalcemia

Abstract

In previous studies, we have shown that prostate secretory protein (PSP-94) can reduce prostate cancer growth in vivo. In the current study, we identified the amino acid sequence of PSP-94 that is required for eliciting this response. For these studies, we used rat prostate cancer Mat Ly Lu cells overexpressing parathyroid hormone-related protein (PTHrP), which is the main pathogenetic factor responsible for hypercalcemia of malignancy. Synthetic peptides corresponding to amino acids 7-21 (PCK721), 31-45 (PCK3145), and 76 -94 (PCK7694) of PSP-94 were synthesized. Only PCK3145 showed a significant reduction in tumor cell proliferation. For in vivo studies, syngenic male Copenhagen rats were inoculated s.c. with Mat Ly Lu cells overexpressing PTHrP into the right flank or into the left ventricle via intracardiac injection, which results in experimental metastases to the lumbar vertebrae causing hind-limb paralysis. Animals were infused with different doses (1, 10, and 100 g/kg/ day) of peptides for 15 days, and the effect of these treatments on tumor volume, skeletal metastases, or development of hind-limb paralysis was determined. Treatment with PCK3145 resulted in a dose-dependent decrease in tumor volume and delay in the development of skeletal metastases. Bone histomorphometry showed that after intracardiac inoculation of tumor cells, the highest dose of PCK3145 (100 g/kg/day) resulted in reducing skeletal tumor burden, which delayed the development of hindlimb paralysis. Treatment with PCK3145 led to reduction of plasma calcium and PTHrP levels and a significant decrease in PTHrP levels in the primary tumors and in vertebrae of experimental animals. These effects of PCK3145 were due to its ability to promote tumor cell apoptosis. Collectively, the results of these studies have demonstrated the ability of a small peptide derived from PSP-94 to reduce tumor volume and experimental skeletal metastases-results that will be highly beneficial in the continued development of this peptide as a novel therapeutic agent for patients with hormone refractory, late-stage prostate cancer.

The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2

“…However, it is well established that the expression of PSP94 progressively decreases during the development of prostate cancer from an early, low-invasive, androgen-dependent state to a late, highly invasive, androgen-refractory state (LaTulippe et al, 2002;Vanaja et al, 2003;Stanbrough et al, 2006). The gradual loss of PSP94 is likely to contribute to the development of prostate cancer because PSP94 impedes prostate cancer growth and metastasis (Garde et al, 1999;Shukeir et al, 2003Shukeir et al, , 2004. The molecular basis for the tumor-suppressor function of PSP94 is complex as this protein has been found to promote tumor cell apoptosis (Garde et al, 1999), to inhibit the secretion of a matrix metalloproteinase that is implicated in tumor metastasis (Annahi et al, 2005), and to decrease tumor-associated, vascular endothelial growth factor (VEGF)-mediated vascularization (Lamy et al, 2006).…”

“…The molecular basis for the tumor-suppressor function of PSP94 is complex as this protein has been found to promote tumor cell apoptosis (Garde et al, 1999), to inhibit the secretion of a matrix metalloproteinase that is implicated in tumor metastasis (Annahi et al, 2005), and to decrease tumor-associated, vascular endothelial growth factor (VEGF)-mediated vascularization (Lamy et al, 2006). Interestingly, the antitumor effects of PSP94 can be recapitulated with a synthetic peptide comprising an N-terminal fragment of PSP94 and this peptide is currently clinically tested for the treatment of metastatic prostate cancer (Shukeir et al, 2004;Annahi et al, 2005;Lamy et al, 2006).…”

Evaluation of the prognostic significance of MSMB and CRISP3 in prostate cancer using automated image analysis

“…It was surprising therefore, to find that the fraction of MSMB-positive cells fell to 10% before the expression correlated with a negative outcome, suggesting that there is a redundancy in protein expression and a fraction of MSMB-expressing cells may be sufficient to maintain any potential tumor suppressing effect(s) that MSMB may exert on tumor cells. Using exogenous MSMB, in vitro and in vivo studies indicate that MSMB may have several antitumor effects on prostate tumor cells, such as suppressing growth and inducing apoptosis; [36][37][38] decreasing metastatic disease, [39][40][41] and inhibiting angiogenesis. 42 Recently, MSMB has gained further attention as a candidate for prostate cancer susceptibility gene, 20,21 and several causal risk alleles affecting the level of gene transcription have been identified in the region upstream of the coding sequence.…”

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

“…ovarian and breast tissue), as revealed by analysis of representative cancer cell lines [73]. In vivo studies indicate that this protein can function as a tumor suppressor [74], and recently the amino acid motif within PSP94 that is required for tumor suppressor function has been identified [75]. Expression of PSP94 is reduced in cancerous prostate tissues in the rat [76].…”