Chemosensitization of Androgen-Independent Prostate Cancer with Neutral Endopeptidase

Makoto Sumitomo, Tomohiko Asano, Junichi Asakuma, Takako Asano, David M. Nanus, Masamichi Hayakawa

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Purpose: We investigated whether neutral endopeptidase (NEP) could augment chemosensitivity to anticancer drugs by promoting protein kinase C (PKC)δ-mediated mitochondrial apoptosis in prostate cancer (PC) cells. Experimental Design: Human PC cell lines LNCaP and PC-3, and a normal prostate epithelial cell line (PrEC) were used. The protein expression was detected by Western blot analysis, and the protein turnover was determined by pulse-chase assay. Apoptotic ratio was measured by annexin V staining. Results: Western blot analyses and pulse-chase assays showed that the specific NEP inhibitor CGS24592 decreased PKCδ protein expression by promoting PKCδ protein degradation in NEP-expressing LNCaP cells. Conversely, recombinant NEP (rNEP) increased PKCδ protein expression by delaying PKCδ protein degradation in NEP-negative PC-3 cells. Apoptosis assays showed that rNEP promoted anticancer drug-induced apoptosis in PC-3 cells specifically through PKCδ activity that mediated anticancer drug-induced mitochondrial change such as cytochrome-c release and caspase-9 activation. Of note, rNEP was able to increase PKCδ protein expression predominantly in PC-3 cells rather than in PrEC cells. Treatment with rNEP before subtoxic concentrations of etoposide (0.1 μM) significantly promoted mitochondrial apoptosis compared with only etoposide in PC-3 cells (P < 0.01) but not in PrEC cells. Conclusions: These results suggest that NEP enzyme activity contributes to anticancer drug-induced PC cell apoptosis dependent on PKCδ-mediated mitochondrial events. More importantly, the combination of NEP with anticancer drugs may be a promising therapeutic modality because rNEP is able to augment chemosensitivity in androgen-independent PC with minimal toxicity in normal tissues.

Original languageEnglish
Pages (from-to)260-266
Number of pages7
JournalClinical Cancer Research
Volume10
Issue number1 I
DOIs
Publication statusPublished - 01-01-2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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