半乳糖凝集素-3通过调节前列腺癌中的雄激素受体信号传导参与肿瘤进展和抗雄激素药物耐药。

Galectin-3 Is Implicated in Tumor Progression and Resistance to Anti-androgen Drug Through Regulation of Androgen Receptor Signaling in Prostate Cancer.

作者信息

Dondoo Tsogt-Ochir, Fukumori Tomoharu, Daizumoto Kei, Fukawa Tomoya, Kohzuki Miho, Kowada Minoru, Kusuhara Yoshito, Mori Hidehisa, Nakatsuji Hiroyoshi, Takahashi Masayuki, Kanayama Hiro-Omi

机构信息

Department of Urology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

Department of Urology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

出版信息

Anticancer Res. 2017 Jan;37(1):125-134. doi: 10.21873/anticanres.11297.

DOI:10.21873/anticanres.11297

PMID:28011482

Abstract

BACKGROUND

Castration-resistant prostate cancer (CRPC)-related deaths are increasing worldwide. Therefore, clarification of the mechanisms of hormone-related tumor progression and resistance to anti-androgen drugs is useful in order to develop strategies for appropriate treatment of CRPC. Galectin-3 has been shown to be correlated with tumor progression in a variety of cancer types through the regulation of tumor proliferation, angiogenesis, and apoptosis.

MATERIALS AND METHODS

We examined tumor cell invasion and migration using the xCELLigence system. Control LNCaP and galectin-3-expressing LNCaP (LNCaP-Gal-3) cells were cultured with androgen-depleted medium with 5% charcoal-stripped serum. Cells were treated for 24 h with or without dihydrotestosterone alone or combined with MDV3100 and bicalutamide; gene profile was then analyzed by microarray analysis and mRNA expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). We evaluated tumor growth using spheroids and xenograft tumor growth in a mouse model.

RESULTS

In vitro, LNCaP-Gal-3 cells promoted both cell migration and invasion in an androgen-independent manner compared to control LNCaP cells. Galectin-3 also enhanced anchorage-independent growth and xenograft tumor growth even after castration. Importantly, galectin-3 greatly enhanced transcriptional activity of the androgen receptor (AR), especially on treatment with dihydrotestosterone. In microarray and qRT-PCR analyses, galectin-3 increased the expression of several AR-target genes, such as kallikrein-related peptidase 3 (KLK3), and transmembrane protease, serine 2 (TMPRSS2). These AR-target genes were not fully suppressed by anti-androgen drugs such as bicalutamide or MDV3100. Galectin-3 significantly inhibited the effect induced by anti-androgen drugs MDV3100 and bicalutamide, suggesting that galectin-3 may be involved in resistance to anti-androgen drug through enhancement of transcriptional activity of AR and expression of AR-related genes.

CONCLUSION

These results suggest that galectin-3 is a potential target molecule for future treatment of anti-androgen drug-resistant prostate cancer.

摘要

背景

去势抵抗性前列腺癌（CRPC）相关的死亡人数在全球范围内呈上升趋势。因此，阐明激素相关肿瘤进展和抗雄激素药物耐药的机制，对于制定CRPC的适当治疗策略很有帮助。已表明半乳糖凝集素-3通过调节肿瘤增殖、血管生成和凋亡，与多种癌症类型的肿瘤进展相关。

材料与方法

我们使用xCELLigence系统检测肿瘤细胞的侵袭和迁移。将对照LNCaP细胞和表达半乳糖凝集素-3的LNCaP（LNCaP-Gal-3）细胞在含5%活性炭处理血清的雄激素剥夺培养基中培养。细胞分别单独用或不用二氢睾酮处理24小时，或与MDV3100和比卡鲁胺联合处理；然后通过微阵列分析分析基因谱，并通过定量实时聚合酶链反应（qRT-PCR）确认mRNA表达。我们使用球体和小鼠模型中的异种移植肿瘤生长来评估肿瘤生长。

结果

在体外，与对照LNCaP细胞相比，LNCaP-Gal-3细胞以雄激素非依赖的方式促进细胞迁移和侵袭。即使在去势后，半乳糖凝集素-3也增强了非锚定依赖性生长和异种移植肿瘤生长。重要的是，半乳糖凝集素-3极大地增强了雄激素受体（AR）的转录活性，尤其是在用二氢睾酮处理时。在微阵列和qRT-PCR分析中，半乳糖凝集素-3增加了几个AR靶基因的表达，如激肽释放酶相关肽酶3（KLK3）和跨膜蛋白酶丝氨酸2（TMPRSS2）。这些AR靶基因未被比卡鲁胺或MDV3100等抗雄激素药物完全抑制。半乳糖凝集素-3显著抑制抗雄激素药物MDV3100和比卡鲁胺诱导的效应，表明半乳糖凝集素-3可能通过增强AR的转录活性和AR相关基因的表达参与抗雄激素药物耐药。