Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence

Stephen J. Libertini, Clifford G. Tepper, Veronica Rodriguez, David M. Asmuth, Hsing Jien Kung, Maria Mudryj

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Prostate carcinoma is the most commonly diagnosed cancer in men and the second leading cause of death due to cancer in Western civilization. Androgen ablation therapy is effective in treating androgen-dependent tumors, but eventually, androgen-independent tumors recur and are refractory to conventional chemotherapeutics. Hence, the emergence of androgen independence is the most challenging problem in managing prostate tumors. We report a novel mechanism of androgen independence: calpain cleaves the androgen receptor (AR) into an androgen-independent isoform. In vitro and in vivo analyses show that calpain removes the COOH-terminal ligand binding domain generating a constitutively active molecule. Analysis of human prostate tumors indicates that several tumors express higher levels of this truncated AR than noncancerous prostate tissue. In transient transfection studies, the truncated AR is three to five times more potent than the full-length receptor in transactivating transcription. The androgen-independent Rv1 cells express high levels of the truncated AR, and treatment of these cells with a calpain inhibitor reduces truncated AR expression. In the absence of androgen, inhibition of calpain activity induces apoptosis. The HIV protease inhibitor amprenavir inhibits calpain activity and is also effective in inducing apoptosis in the Rv1 cell line. The cell culture studies were reproduced in a mouse xenograft model, where, in the absence of androgens, amprenavir significantly reduces tumor growth. Together, these studies indicate that calpain-dependent proteolysis of the AR may be a mechanism of androgen independence. The calpain inhibition studies suggest that inhibiting this activity may be a potential treatment for some androgen-independent prostate tumors.

Original languageEnglish
Pages (from-to)9001-9005
Number of pages5
JournalCancer Research
Volume67
Issue number19
DOIs
Publication statusPublished - Oct 1 2007
Externally publishedYes

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Calpain
Androgen Receptors
Androgens
Prostate
Neoplasms
Apoptosis
HIV Protease Inhibitors
Civilization
Heterografts
Proteolysis
Transfection
Cause of Death
Protein Isoforms
Cell Culture Techniques
Ligands
Carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. / Libertini, Stephen J.; Tepper, Clifford G.; Rodriguez, Veronica; Asmuth, David M.; Kung, Hsing Jien; Mudryj, Maria.

In: Cancer Research, Vol. 67, No. 19, 01.10.2007, p. 9001-9005.

Research output: Contribution to journalArticle

Libertini, Stephen J. ; Tepper, Clifford G. ; Rodriguez, Veronica ; Asmuth, David M. ; Kung, Hsing Jien ; Mudryj, Maria. / Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. In: Cancer Research. 2007 ; Vol. 67, No. 19. pp. 9001-9005.
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