Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Prostate cancer remains a significant health concern, often treated with androgen deprivation (AD).
• Novel therapeutic strategies are needed to overcome resistance and improve treatment efficacy.
• Edelfosine, a synthetic alkyl-lysophospholipid, exhibits antitumor properties.

Purpose of the Study:

• To investigate the combined effects of edelfosine and AD on prostate cancer cells (LNCaP and VCaP).
• To elucidate the underlying molecular mechanisms of this combination therapy.
• To evaluate the in vivo efficacy of edelfosine plus AD.

Main Methods:

• Cell proliferation assays, apoptosis assays, Western blotting, and reporter gene assays were performed.
• Small interfering RNA (siRNA) was used to knockdown ATF3.
• In vivo studies utilized an orthotopic LNCaP xenograft model.

Main Results:

• Edelfosine plus AD significantly inhibited cell proliferation and increased apoptosis compared to single agents.
• Edelfosine decreased AKT activity and inhibited androgen receptor (AR) expression.
• ATF3 was upregulated, bound to AR, and repressed AR transactivation, mediating edelfosine's growth inhibition.
• AR variant 7 (ARv7) and TMPRSS2-ERG fusion gene expression were inhibited.
• In vivo, combined treatment significantly reduced tumor volume and PSA levels.

Conclusions:

• Edelfosine in combination with AD demonstrates potent antitumor activity against prostate cancer.
• The mechanism involves ATF3-mediated repression of AR transactivation.
• This combination therapy holds promise for clinical application in prostate cancer treatment.