New Modes of GPCR Signalling

IGF-1 Promote BPH-1 Cell Proliferation Primarily via Activating
mTOR-dependent Translational Increases in Cyclin D Proteins
Ke Gong, Chao Chen and Wenhua Li*
Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan
430072, PR China.
Aim: Insulin-like growth factor-1 (IGF-1) and its binding protein (IGFBP-3) play a
crucial role in the initiation and progression of prostate and benign prostatic hyperplasia
(BPH). We have previously report that stromally expressed c-Jun protein modulates the
epithelial proliferation via regulating production and paracrine signals of IGF-1, which
promote the BPH-1 cells proliferation through upregulate cyclin D protein levels.
Methods: Western blots analyses for protein levels and cell cycle array of FACS were
performed. Results: In this study, the exact molecular mechanisms of these regulations
were investigated. We found that IGF-1 increases cyclin D proteins and promotes cell
cycle transition from G0 to S phase, bringing in cell proliferation. IGF-1 almost didn’t
affects cyclin D mRNA levels and it primarily stimulates post-transcriptional increases
in cyclin D proteins. IGF-1 stimulation increases cyclin D protein in translation levels
via activation mammalian target of rapamycin (mTOR) pathway in BPH-1 cells. Two
vital factors of mTOR-downstream, the eukaryotic translation initiation factor-4E
binding protein-1 (4EBP1) and 70-kD ribosomal protein S6 kinase (p70S6K), were
activated after IGF-1 treatment. Blocking mTOR will decrease cyclin D levels and
offset IGF-1 stimulation. Moreover, we found that, in BPH-1cells, activated mTOR by
IGF-1 increases cyclin D protein expression is mediated through activation of the
PI3K/Akt pathways cells, but not MAP kinase pathway. Also, our data indicate that
IGF-1 probably influences the combination of cyclin D and ubiquitin, and then stabilize
the cyclin D protein. Conclution: These results elucidate the molecular transduction
pathways of IGF-1 promote BPH-1 cell proliferation, which will be help to improve our
understanding of BPH and develop new clinical therapy for it.
Key Words: IGF-1; BPH; mTOR; cyclinD
*Corresponding Authors:
Wenhua Li, Email: whli@whu.wdu.cn, Tel: 86-27-68756711