Casein kinase 2 inhibition attenuates androgen receptor function and cell proliferation in prostate cancer cells

The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA1, LPA2, and LPA3. We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA1 gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA1 gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA1 and do not proliferate in response to LPA stimulation, implying LPA1 transduces cell growth signals. Accordingly, stable expression of LPA1 in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA1 cells resulted in increased rate of tumor growth in animals compared with those tumors that developed from the wild-type cells. Growth of LNCaP cells depends on androgen receptor activation, and we show that LPA1 transduces Gαi-dependent signals to promote nuclear localization of androgen receptor and cell proliferation. In addition, treatment with bicalutamide inhibited LPA-induced cell cycle progression and proliferation of LNCaP-LPA1 cells. These results suggest the possible utility of LPA1 as a drug target to interfere with progression of prostate cancer.

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Biologic activity of LSD1 inhibition by novel tranylcypromine structural analogues in prostate cancer cells.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.82 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 82-82

Author(s):

Simon J. Crabb ◽

Annette L Hayden ◽

Rosemary A Strivens ◽

Hanae Benelkebir ◽

A Ganesan ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Androgen Receptor ◽

Cancer Cells ◽

Specific Antigen ◽

Histone H3 ◽

Prostate Cancer Cells ◽

Poor Prognostic Factor ◽

Structural Analogues ◽

Chemical Inhibition

82 Background: Hormonal strategies to inhibit androgen receptor (AR) signalling remain inadequate and so novel approaches are urgently required. Lysine (K)-specific demethylase 1A (LSD1), is an epigenetic AR co-activator which modifies chromatin structure through de-methylation of histone H3 lysine 9 at androgen response elements to activate transcriptional expression of AR target genes. LSD1 is over-expressed and a poor prognostic factor in prostate cancer. We have synthesised novel analogues of the monoamine oxidase (MAO) inhibitor tranylcypromine as LSD1 inhibitors to exploit MAO and LSD1 sequence homology. Methods: We utilised prostate cancer cell line models to investigate the biological effect of LSD1 inhibition using tranylcypromine analogues. Results: Chemical inhibition of LSD1 was effective in inhibiting cell proliferation in prostate cancer models with around 1000 fold greater potency for synthesised analogues over tranylcypromine in LNCaP prostate cancer cells. Chemical inhibition of LSD1 induced the predicted histone methylation changes consequent on LSD1 inhibition of mono- and di-methylation of histone H3 lysine 9. In addition LSD1 depletion, AR depletion and reduced expression of the AR target gene prostate-specific antigen was demonstrated. Fractional effect assays demonstrated synergistic interactions in cell proliferation assays for tranylcypromine analogues with the androgen receptor antagonists bicalutamide and MDV3100. Conclusions: Our data demonstrate biological activity of LSD1 inhibition in prostate cancer cells with depletion of AR signalling using optimised structural analogues of established drugs for non-cancer indications. Therapeutic targeting of LSD1 for prostate cancer would represent a novel therapeutic paradigm for this disease.

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