High-Density Lipoprotein Induces Proliferation and Migration of Human Prostate Androgen–Independent Cancer Cells by an ABCA1-Dependent Mechanism

Abstract

Androgen deprivation therapy for prostate cancer leads to a significant increase of high-density lipoprotein (HDL), which is generally viewed as beneficial, particularly for cardiovascular disease, but the effect of HDL on prostate cancer is unknown. In this study, we investigated the effect of HDL on prostate cancer cell proliferation, migration, intracellular cholesterol levels, and the role of cholesterol transporters, namely ABCA1, ABCG1, and SR-BI in these processes. HDL induced cell proliferation and migration of the androgenindependent PC-3 and DU145 cells by a mechanism involving extracellular signal-regulated kinase (ERK) 1/2 and Akt, but had no effect on the androgen-dependent LNCaP cell, which did not express ABCA1 unlike the other cell lines. Treatment with HDL did not significantly alter the cholesterol content of the cell lines. Knockdown of ABCA1 but not ABCG1 or SR-BI by small interfering RNA (siRNA) inhibited HDL-induced cell proliferation, migration, and ERK1/2 and Akt signal transduction in PC-3 cells. Moreover, after treatment of LNCaP cells with charcoal-stripped fetal bovine serum, ABCA1 was induced ∼10-fold, enabling HDL to induce ERK1/2 activation, whereas small interfering RNA knockdown of ABCA1 inhibited HDL-induced ERK1/2 activation. Simvastatin, which inhibited ABCA1 expression in PC-3 and DU145 cells, attenuated HDL-induced PC-3 and DU145 cell proliferation, migration, and ERK1/2 and Akt phosphorylation. In human prostate biopsy samples, ABCA1 mRNA expression was ∼2-fold higher in the androgen deprivation therapy group than in subjects with benign prostatic hyperplasia or pretreatment prostate cancer groups. In summary, these results suggest that HDL by an ABCA1-dependent mechanism can mediate signal transduction, leading to increased proliferation and migration of prostate cancer cells. Mol Cancer Res; 8(9); 1284-94. ©2010 AACR.

Cross-talk between the Androgen Receptor and the Liver X Receptor

“…This correlates with in vivo findings, including reduced ABCA1 expression when hypogonodal (androgen-deficient) mice were treated with testosterone (49), increased ABCA1/G1 expression in PCa xenografts when mice were treated with the androgen synthesis inhibitor dutasteride (50), and increased ABCA1 mRNA levels in PCa tissues from patients receiving androgen deprivation therapy (38). Thus, the cross-talk between AR and LXR is observed in vivo and hence has biological relevance.…”

Long non-coding RNAs in cancer invasion and metastasis

“…32 One study identified a set of genes that might act to promote lung cancer metastasis, reporting that the expression of these genes depends on MALAT1. [34][35][36][37] These MALAT1 target genes were either associated with metastasis or represented critical regulators of metastasis establishment, and were strongly reduced by the loss of MALAT1. 34 These reports support the hypothesis that MALAT1 is an activator of metastasis and affects metastatic processes.…”

Is the Good Cholesterol Bad for Prostate cancer?

“…HDL, which is generally viewed as beneficial, particularly for cardiovascular disease, but the effect of HDL on prostate cancer is unknown [15].…”

“…HDL by an ABCA1-dependent mechanism can mediate signal transduction, leading to increased proliferation and migration of prostate cancer cells. [15].…”