Premium
The role of insulin‐like growth factor binding protein‐3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells
Author(s) -
Peng Lihong,
Wang Jining,
Malloy Peter J.,
Feldman David
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23100
Subject(s) - lncap , endocrinology , medicine , cell growth , biology , androgen , insulin like growth factor binding protein , growth inhibition , androgen receptor , growth factor , cancer research , prostate cancer , insulin like growth factor , cancer , hormone , receptor , biochemistry
Insulin‐like growth factor binding protein‐3 (IGFBP‐3), an antiproliferative and proapoptotic protein, has been shown to be upregulated by growth inhibitory concentrations of androgens in LNCaP human prostate cancer (PCa) cells, but the mechanism of regulation and the role of IGFBP‐3 in the modulation of PCa cell proliferation are unknown. In this study, we have examined the effects of a range of concentrations of the synthetic androgen R1881 on IGFBP‐3 expression and cell growth in LNCaP cells. We have also investigated the role of androgen‐stimulated IGFBP‐3 in androgen‐induced growth inhibition. We show that low doses of R1881 stimulate LNCaP cell proliferation, but do not induce IGFBP‐3 expression, whereas high doses of R1881 that inhibit cell growth, significantly increase expression of IGFBP‐3. Importantly, we demonstrate that the combination of calcitriol and androgens not only synergistically upregulates IGFBP‐3 expression but also inhibits cell growth better than either hormone alone. siRNA knockdown of IGFBP‐3 expression partially reverses the growth inhibition by calcitriol and by androgens. Furthermore, we find that the growth inhibitory dose of R1881 leads to increases in the cyclin dependent kinase inhibitors (CDKIs), p21 and p27 as well as to G1 arrest. These changes can be blocked or partially reversed by IGFBP‐3 siRNA, indicating that the induction of CDKIs is downstream of IGFBP‐3. Our data suggest, for the first time, that IGFBP‐3 is involved in the antiproliferative action of high doses of androgens partly through p21 and p27 pathways and that IGFBP‐3 may contribute significantly to androgen‐induced changes in LNCaP cell growth. © 2007 Wiley‐Liss, Inc.