ERK regulates calpain 2-induced androgen receptor proteolysis in CWR22 relapsed prostate tumor cell lines

Honglin Chen, Stephen J. Libertini, Yu Wang, Hsing-Jien Kung, Paramita M Ghosh, Maria Mudryj

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Androgen ablation therapy is effective in treating androgendependent prostate tumors; however, tumors that can proliferate in castrate levels of androgen eventually arise.Wepreviously reported that in CWR22Rv1 (Rv1) cells, the protease calpain 2 can cleave the androgen receptor (AR) into a constitutively active ∼80,000 low molecular weight(LMW)form. In this study, we further dissect the mechanisms that produce the AR LMW forms using Rv1 cells and the related CWR22-R1 (R1) cells. The 39-amino acid insertional mutation in the Rv1-AR (E3DM-AR) sensitizes this AR to calpain 2 proteolysis. R1 cells encode the same AR molecule as the parental CWR22 xenograft. Using calpain 2 small interfering RNA and calpeptin, we find that calpain 2 plays a role in the generation of the LMW-AR in R1 cells. Furthermore, LMW-AR expression is regulated by the activation of calpain 2 by ERK 1 and 2. Inhibition of ERK phosphorylation or small interfering RNA-mediated decrease of ERK expression reducesLMW-ARlevels in R1 cells. Conversely, activation of the MAPK pathway results in increased ERK phosphorylation and increased levels of LMW-AR. Finally, analyses of human tumor samples found that LMW-AR levels are higher in tumors that have an increased calpain/calpastatin ratio and/or increased levels of phospho-ERK (pERK). This suggests that a higher calpain/calpastatin ratio collaborates with activated ERK to promote the generation of the LMW-AR.

Original languageEnglish (US)
Pages (from-to)2368-2374
Number of pages7
JournalJournal of Biological Chemistry
Volume285
Issue number4
DOIs
StatePublished - Jan 22 2010

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Proteolysis
Calpain
Androgen Receptors
Tumor Cell Line
Tumors
Prostate
Cells
Molecular Weight
Molecular weight
Phosphorylation
Small Interfering RNA
Androgens
Neoplasms
Chemical activation
Ablation
Heterografts
Peptide Hydrolases

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

ERK regulates calpain 2-induced androgen receptor proteolysis in CWR22 relapsed prostate tumor cell lines. / Chen, Honglin; Libertini, Stephen J.; Wang, Yu; Kung, Hsing-Jien; Ghosh, Paramita M; Mudryj, Maria.

In: Journal of Biological Chemistry, Vol. 285, No. 4, 22.01.2010, p. 2368-2374.

Research output: Contribution to journalArticle

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