Transforming growth factor-β (TGFβ) regulates proliferation, differentiation and differentiated function in a wide variety in cells. In prostate cancer cells, TGFβ inhibits proliferation in the earlier stages; however the cancer cells become refractory to growth inhibitory effects in advanced stages where TGFβ promotes cancer progression and metastasis. Intracellular mechanisms involved in these varied effects of TGFβ on prostate cancer cells are poorly understood. Inhibitor of Differentiation (Id) family of closely related proteins (Id1, Id2, Id3, Id4) inhibit binding of bHLH transcription factors to DNA and inhibit their effects on cell proliferation and differentiation. In the present study, we have investigated the involvement of Id1 and Id3 proteins in the effects of TGFβ on prostate cancer cells. Id1 and Id3 isoforms of protein are expressed in DU145 cells, which have previously been shown to be responsive to growth inhibitory effects of TGFβ. TGFβ caused a significant increase of protein levels of Id1 and Id3 as determined by Western blot analyses. This early induction was followed by a late downregulation of Id1, while Id3 induction remained stable. However in PC3 cells, this early induction of Id1 and Id3 proteins remained stable. Proliferation marker p21 was also induced in DU145 cells, while p21 protein was undetected in PC3 cells upon TGFβ1 treatment. Since previous studies have revealed that the loss of Id1 or Id3 is indicative of loss of proliferation in prostate cancer, Id1 effects were further studied between DU145 and PC3 cell lines. Id1 knockdown in DU145 cells resulted in enhanced inhibitory effects of TGFβ on cell proliferation. However, Id1 knockdown in PC3 did not influence TGFβ effects on proliferation. These results indicate that Id1 downregulation by TGFβ may be required for its effects on proliferation in DU145 cancer cells. We next investigated TGFβ effects on migration in PC3 cells, which TGFβ stimulation has been shown to increase its migration properties. Both Id1 and Id3 knockdown in PC3 cells decreased migratory response to TGFβ. This indicated that both Id1 and Id3 are necessary for TGFβ migratory properties of PC3 cells. Taken together, these results show that Id1 and Id3 act as necessary proteins in the TGFβ pathway on both proliferation and migration. Grant support: NIH 1P20MD002285-02 and RCMI G12RR03602

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1076. doi:1538-7445.AM2012-1076