Anticancer Effects of Tetracyclines in LNCaP Prostate Cancer Cells

Abstract

The tetracycline family includes tetracycline, doxycycline and minocycline, all of which have been used as antibiotics effectively for decades. The biologic actions of tetracyclines affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism have been researched. Recently, several studies showed anticancer effects of tetracyclines in various cancer cells. However, the mechanism for the anticancer effect of tetracyclines are still not clearly understood. The androgen receptor (AR) is a ligand-dependent transcription factor which plays a central role in male sexual development and differentiation. In addition to this physiologic function, AR plays a prominent role in the pathogenesis of human prostate cancer. In this study, the anticancer effects of tetracyclines were investigated in prostate cancer cells. Tetracycline, doxycycline and minocycline inhibited the growth of LNCaP cells, but did not induce growth inhibition in DU145 and PC3 cells. Treatment of LNCaP cells with minocycline resulted in G1 cell cycle arrest, increasing p21 and p27 and decreasing expression of CDK 2, CDK 4, cyclin A, cyclin D1, cyclin E and dephosphorylation of retinoblastoma protein. Minocycline reduced the transcriptional activity of AR and the expression of AR-target molecules prostate-specific antigen (PSA) and Nkx3.1. Moreover, minocycline inhibited androgen-induced cell proliferation and transcriptional activity of AR. These findings suggest that tetracyclines have growth inhibitory effects on androgen-dependent prostate cancer cells and provide evidence that tetracyclines may be an effective therapeutic strategy for targeting androgen-dependent prostate cancer.

Tetarcycline, doxycycline, minocycline은 tetracycline 유도체로 항균 효과를 가지는 물질이며 염증, 혈관신생과 세포사멸을 조절하는 효과가 있다고 알려져 있으며, 최근 다양한 암 세포에서 항암효과가 보고되고 있다. 그러나 그 항암기전에 대해서는 정확히 알려져 있지 않다. 이 연구에서는 LNCaP, DU145, PC3 전립선암 세포주를 사용하여 tetracycline 유도체의 항암 효과에 대해 조사하였다. Tetracycline, doxycycline, minocycline은 DU145와 PC3 세포주에서는 성장 억제 효과가 없었으나 androgen-dependent 세포주인 LNCaP 세포주에서는 세포 성장을 억제하였다. Minocycline는 LNCaP 세포주에서 세포 주기 중 G1기를 증가시켰으며, 이는 세포 주기 조절 단백질인 CDKI (p21과 p27) 단백질의 증가와 CDK 2, CDK 4, cyclin A, cycline D1, cyclin E의 감소와 retinoblastoma 단백질의 인산화를 감소와 관련이 있었다. 또한 minocycline은 androgen response element promoter assay에서 androgen receptor의 전사 활성 감소와 androgen receptor의 target 유전자인 prostate-specific antigen과 Nkx3.1의 mRNA 발현을 감소시켰다. 이러한 결과를 종합해 볼 때 minocycline은 androgen-dependent 전립선 암세포주에서 세포 주기 조절을 통한 세포 성장 억제 효과를 가지며 이는 androgen receptor 전사 활성 억제와 관련이 있는 것으로 생각된다.