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N-Terminal Domain Mediated Regulation of ROR?1 Inhibits Invasive Growth in Prostate Cancer.

ABSTRACT: Four members of the retinoic acid-related orphan receptor ? (ROR?) family (ROR?1, ROR?2, ROR?3 and ROR?4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, ROR?1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of ROR?1 that potentiated the downregulation of target genes involved in tumor progression and proliferation, based on results from ROR?-deficient mouse embryonic fibroblasts and prostate carcinoma tissues. The hyperactivation of proliferative target genes were observed in ROR?-deficient embryonic fibroblasts, and reconstitution of ROR?1 inhibited this activation by a NTD dependent manner. Downregulation of ROR?1 and upregulation of Wnt/?-catenin target genes were correlated in prostate cancer patients. These findings revealed the control of invasive growth by NTD-mediated ROR?1 signaling, suggesting advanced approaches for the development of therapeutic drugs.

SUBMITTER: Park SC

PROVIDER: S-EPMC6479703 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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N-Terminal Domain Mediated Regulation of RORα1 Inhibits Invasive Growth in Prostate Cancer.

Park Su Chan SC Park Il-Geun IG Kim Hyunkyung H Lee Ji Min JM

International journal of molecular sciences 20190404 7

Four members of the retinoic acid-related orphan receptor α (RORα) family (RORα1, RORα2, RORα3 and RORα4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, RORα1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of RORα1 that potentiated the downregulation of target genes involved in tumor ...[more]

PMID: 30987323

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Project description:BackgroundHeparin affin regulatory peptide (HARP), also called pleiotrophin, is a heparin-binding, secreted factor that is overexpressed in several tumours and associated to tumour growth, angiogenesis and metastasis. The C-terminus part of HARP composed of amino acids 111 to 136 is particularly involved in its biological activities and we previously established that a synthetic peptide composed of the same amino acids (P111-136) was capable of inhibiting the biological activities of HARP. Here we evaluate the ability of P111-136 to inhibit in vitro and in vivo the growth of a human tumour cell line PC-3 which possess an HARP autocrine loop.MethodsA total lysate of PC-3 cells was incubated with biotinylated P111-136 and pulled down for the presence of the HARP receptors in Western blot. In vitro, the P111-136 effect on HARP autocrine loop in PC-3 cells was determined by colony formation in soft agar. In vivo, PC-3 cells were inoculated in the flank of athymic nude mice. Animals were treated with P111-136 (5 mg/kg/day) for 25 days. Tumour volume was evaluated during the treatment. After the animal sacrifice, the tumour apoptosis and associated angiogenesis were evaluated by immunohistochemistry. In vivo anti-angiogenic effect was confirmed using a mouse Matrigel™ plug assay.ResultsUsing pull down experiments, we identified the HARP receptors RPTPβ/ζ, ALK and nucleolin as P111-136 binding proteins. In vitro, P111-136 inhibits dose-dependently PC-3 cell colony formation. Treatment with P111-136 inhibits significantly the PC-3 tumour growth in the xenograft model as well as tumour angiogenesis. The angiostatic effect of P111-136 on HARP was also confirmed using an in vivo Matrigel™ plug assay in miceConclusionsOur results demonstrate that P111-136 strongly inhibits the mitogenic effect of HARP on in vitro and in vivo growth of PC-3 cells. This inhibition could be linked to a direct or indirect binding of this peptide to the HARP receptors (ALK, RPTPβ/ζ, nucleolin). In vivo, the P111-136 treatment significantly inhibits both the PC-3 tumour growth and the associated angiogenesis. Thus, P111-136 may be considered as an interesting pharmacological tool to interfere with tumour growth that has now to be evaluated in other cancer types.

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N-Terminal Domain Mediated Regulation of ROR?1 Inhibits Invasive Growth in Prostate Cancer.

Publications

N-Terminal Domain Mediated Regulation of RORα1 Inhibits Invasive Growth in Prostate Cancer.

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