PAR1-mediated NFκB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism

Kwanchanit Tantivejkul, Robert D. Loberg, Samkeliso C. Mawocha, Lashon L. Day, Lauren St. John, Brian A. Pienta, Mark A. Rubin, Kenneth J. Pienta

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously reported that protease-activated receptor 1 (PAR1 or thrombin receptor) is overexpressed in metastatic prostate cancer cell lines compared to prostate epithelial cells. In this study, we examined 1,074 prostate biopsies by tissue microarray analysis and demonstrated that PAR1 expression is significantly increased in prostate cancer compared to normal prostate epithelial cells and benign prostatic hyperplasia. We hypothesized that PAR1 activation contributed to prostate cancer cell progression. We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen-independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFκB p65 subunit. IL-6 and IL-8 levels were also elevated in conditioned media by at least two-fold within 4-6 h of PAR1 activation. This induction of cytokine production was abrogated by pretreatment of cells with the NFκB inhibitor caffeic acid phorbol ester. The p38 and ERK1/2 MAPK signaling cascades were also activated by PAR1 stimulation, whereas the SAPK/JNK pathway was unaffected. Inhibition of p38 and ERK1/2 by SB-203589 and PD-098059, respectively, did not abrogate NFκB activity, suggesting an independent induction of NFκB by PAR1 stimulation. Furthermore, TUNEL assay showed that activation of PAR1 attenuated docetaxel induced apoptosis through the upregulation of the Bcl-2 family protein Bcl-xL. Akt activation was not observed, suggesting that drug resistance induced by PAR1 was independent of PI3K signaling pathway. Because thrombin and PAR1 are over-expressed in prostate cancer patients, targeting the inhibition of their interaction may attenuate NFκB signaling transduction resulting in decreased drug resistance and subsequent survival of prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)641-652
Number of pages12
JournalJournal of cellular biochemistry
Volume96
Issue number3
DOIs
StatePublished - Oct 15 2005

Keywords

  • Bcl-xL
  • Cytokines
  • PAR1
  • Prostate cancer
  • Survival

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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