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Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2.
Mol Cancer Res 2008; 6(6):1043-51MC

Abstract

A major characteristic of prostate cancer is the elevation of serum levels of prostate-specific antigen (hK3) and hK2, which are tumor markers that correlate with advancing stages of disease. Including hK4, these three kallikrein serine proteases are almost exclusively produced by the prostate. Prostate cancer cells have been recently shown to overexpress protease-activated receptors (PAR), which can be potentially activated by kallikreins and can regulate tumor growth. Here, we show that recombinant hK2 and hK4 activate ERK1/2 signaling of DU-145, PC-3, and LNCaP prostate cancer cells, which express both PAR1 and PAR2. These kallikreins also stimulate the proliferation of DU-145 cells. Pretreatment of hK2 and hK4 with the serine protease inhibitor, aprotinin, blocks the responses in DU-145 cells, and small interfering RNA against PAR1 and PAR2 also inhibits ERK1/2 signaling. To determine which PAR is activated by hK2 and hK4, a cell line that expresses a single PAR, a PAR1 knockout mouse lung fibroblast cell line transfected with PAR1 (KOLF-PAR1) or PAR2 (KOLF-PAR2) was used. hK4 activates both PAR1 and PAR2, whereas hK2 activates PAR2. hK4 generates more phosphorylated ERK1/2 than hK2. These data indicate that prostatic kallikreins (hK2 and hK4) directly stimulate prostate cancer cell proliferation through PAR1 and/or PAR2 and may be potentially important targets for future drug therapy for prostate cancer.

Authors+Show Affiliations

Department of Urology, University of Washington, Box 356510, Seattle, WA 98195, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18567807

Citation

Mize, Gregory J., et al. "Prostate-specific Kallikreins-2 and -4 Enhance the Proliferation of DU-145 Prostate Cancer Cells Through Protease-activated Receptors-1 and -2." Molecular Cancer Research : MCR, vol. 6, no. 6, 2008, pp. 1043-51.
Mize GJ, Wang W, Takayama TK. Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. Mol Cancer Res. 2008;6(6):1043-51.
Mize, G. J., Wang, W., & Takayama, T. K. (2008). Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. Molecular Cancer Research : MCR, 6(6), pp. 1043-51. doi:10.1158/1541-7786.MCR-08-0096.
Mize GJ, Wang W, Takayama TK. Prostate-specific Kallikreins-2 and -4 Enhance the Proliferation of DU-145 Prostate Cancer Cells Through Protease-activated Receptors-1 and -2. Mol Cancer Res. 2008;6(6):1043-51. PubMed PMID: 18567807.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. AU - Mize,Gregory J, AU - Wang,Wenbin, AU - Takayama,Thomas K, PY - 2008/6/24/pubmed PY - 2008/8/30/medline PY - 2008/6/24/entrez SP - 1043 EP - 51 JF - Molecular cancer research : MCR JO - Mol. Cancer Res. VL - 6 IS - 6 N2 - A major characteristic of prostate cancer is the elevation of serum levels of prostate-specific antigen (hK3) and hK2, which are tumor markers that correlate with advancing stages of disease. Including hK4, these three kallikrein serine proteases are almost exclusively produced by the prostate. Prostate cancer cells have been recently shown to overexpress protease-activated receptors (PAR), which can be potentially activated by kallikreins and can regulate tumor growth. Here, we show that recombinant hK2 and hK4 activate ERK1/2 signaling of DU-145, PC-3, and LNCaP prostate cancer cells, which express both PAR1 and PAR2. These kallikreins also stimulate the proliferation of DU-145 cells. Pretreatment of hK2 and hK4 with the serine protease inhibitor, aprotinin, blocks the responses in DU-145 cells, and small interfering RNA against PAR1 and PAR2 also inhibits ERK1/2 signaling. To determine which PAR is activated by hK2 and hK4, a cell line that expresses a single PAR, a PAR1 knockout mouse lung fibroblast cell line transfected with PAR1 (KOLF-PAR1) or PAR2 (KOLF-PAR2) was used. hK4 activates both PAR1 and PAR2, whereas hK2 activates PAR2. hK4 generates more phosphorylated ERK1/2 than hK2. These data indicate that prostatic kallikreins (hK2 and hK4) directly stimulate prostate cancer cell proliferation through PAR1 and/or PAR2 and may be potentially important targets for future drug therapy for prostate cancer. SN - 1541-7786 UR - https://www.unboundmedicine.com/medline/citation/18567807/Prostate_specific_kallikreins_2_and__4_enhance_the_proliferation_of_DU_145_prostate_cancer_cells_through_protease_activated_receptors_1_and__2_ L2 - http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18567807 DB - PRIME DP - Unbound Medicine ER -