Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells

Sanchez, Washington Y., de Veer, Simon J., Swedberg, Joakim E., Hong, Eui-Ju, Reid, Janet C., Walsh, Terry P., Hooper, John D., Hammond, Geoffrey L., Clements, Judith A. and Harris, Jonathan M. (2012) Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells. Endocrinology, 153 7: 3179-3189. doi:10.1210/en.2012-1011

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
UQ340634_fulltext.pdf Full text (open access) application/pdf 960.02KB 0

Author Sanchez, Washington Y.
de Veer, Simon J.
Swedberg, Joakim E.
Hong, Eui-Ju
Reid, Janet C.
Walsh, Terry P.
Hooper, John D.
Hammond, Geoffrey L.
Clements, Judith A.
Harris, Jonathan M.
Title Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells
Journal name Endocrinology   Check publisher's open access policy
ISSN 0013-7227
1945-7170
Publication date 2012-04-01
Year available 2012
Sub-type Article (original research)
DOI 10.1210/en.2012-1011
Open Access Status File (Author Post-print)
Volume 153
Issue 7
Start page 3179
End page 3189
Total pages 11
Place of publication Chevy Chase United States
Publisher The Endocrine Society
Language eng
Subject 1310 Endocrinology
Formatted abstract
Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormonebinding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact.

Characterization of this proteolysis fragment by [3H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.
Keyword Endocrinology & Metabolism
Endocrinology & Metabolism
ENDOCRINOLOGY & METABOLISM
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 497270
PR09
44323
MOP-15261
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 5 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 6 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 27 Sep 2014, 05:15:15 EST by System User on behalf of Mater Research Institute-UQ