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Inhibitory effects of nordihydroguaiaretic acid (NDGA) on the IGF‐1 receptor and androgen dependent growth of LAPC‐4 prostate cancer cells
Author(s) -
Ryan Charles J.,
Zavodovskaya Marianna,
Youngren Jack F.,
Campbell Michael,
Diamond Marc,
Jones Jeremy,
Shiry Laura,
Allan Geoffrey,
Maddux Betty A.,
Goldfine Ira D.
Publication year - 2008
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20789
Subject(s) - androgen receptor , nordihydroguaiaretic acid , endocrinology , androgen , medicine , dihydrotestosterone , prostate cancer , growth inhibition , biology , cell growth , prostate , cancer research , chemistry , cancer , biochemistry , hormone , arachidonic acid , enzyme
BACKGROUND Nordihydroguaiaretic acid (NDGA) is an inhibitor of the IGF‐1 receptor (IGF‐1R) in breast and other cancers, and concomitantly inhibits tumor growth both in cultured cells and animals. The current study evaluates the effect of NDGA on the androgen‐stimulated growth of human prostate cancer cells. METHODS LAPC‐4 prostate cancer cells in tissue culture were androgen starved for 3 days, 1 nM dihydrotestosterone (DHT) and other androgens were then added for up to 7 days, and cell proliferation measured. IGF‐1R protein expression was measured by Western blot, and IGF‐1R mRNA expression by quantitative PCR. IGF‐1R receptor kinase activation was measured by ELISA. RESULTS After 7 days, LAPC‐4 growth was doubled by 1 nM DHT. NDGA had a rapid effect to inhibit IGF‐1R autophosphorylation induced by IGF‐1. DHT increased the expression of IGF‐1R protein and mRNA levels. Maximal IGF‐1R protein levels were observed 3 days after the addition of androgen. In addition, NDGA, at 10 µM or less, inhibited DHT‐induced proliferation in both cells grown in plates and cells grown in soft agar. Androgen receptor (AR) studies by FRET revealed that NDGA had no conformational effects on the AR in response to ligand. CONCLUSIONS NDGA blocks the DHT‐induced growth of LAPC‐4 prostate cancer cells by several mechanisms including rapid inhibition of the IGF‐1R kinase, and a dose‐dependent inhibition of androgen stimulation of IGF‐1R expression. Clinical studies of this agent will determine its efficacy in the setting of androgen‐dependent prostate cancer. Prostate 68: 1232–1240, 2008. © 2008 Wiley‐Liss, Inc.