Institute of Biomedical Technology, State University of New York, Binghamton, NY, USA.
Prostate Cancer Prostatic Dis. 2010 Jun;13(2):151-61. doi: 10.1038/pcan.2009.59. Epub 2010 Jan 12.
Cryoablation has emerged as a primary therapy to treat prostate cancer. Although effective, the assumption that freezing serves as a ubiquitous lethal stress is challenged by clinical experience and experimental evidence demonstrating time-temperature-related cell-death dependence. The age-related transformation from an androgen-sensitive (AS) to an androgen-insensitive (AI) phenotype is a major challenge in the management of prostate cancer. AI cells exhibit morphological changes and treatment resistance to many therapies. As this resistance has been linked with alpha6beta4 integrin overexpression as a result of androgen receptor (AR) loss, we investigated whether alpha6beta4 integrin expression, as a result AR loss, contributes to the reported increased freeze tolerance of AI prostate cancer. A series of studies using AS (LNCaP LP and PC-3 AR) and AI (LNCaP HP and PC-3) cell lines were designed to investigate the cellular mechanisms contributing to variations in freezing response. Investigation into alpha6beta4 integrin expression revealed that AI cell lines overexpressed this protein, thereby altering morphological characteristics and increasing adhesion characteristics. Molecular investigations revealed a significant decrease in caspases-8, -9, and -3 levels in AI cells after freezing. Inhibition of alpha6beta4 integrin resulted in increased caspase activity after freezing (similar to AS cells) and enhanced cell death. These data show that AI cells show an increase in post-freeze susceptibility after inhibition of alpha6beta4 integrin function. Further understanding the role of androgen receptor-related alpha6beta4 integrin expression in prostate cancer cells responses to freezing might lead to novel options for neo-adjunctive treatments targeting the AR signaling pathway.
冷冻消融已成为治疗前列腺癌的主要手段。虽然有效，但冷冻作为普遍致命应激的假设受到临床经验和实验证据的挑战，这些证据表明细胞死亡与时间-温度有关。与雄激素敏感（AS）向雄激素不敏感（AI）表型的年龄相关转化是前列腺癌管理的主要挑战。AI 细胞表现出形态变化和对许多治疗方法的耐药性。由于这种耐药性与雄激素受体（AR）丧失导致的 alpha6beta4 整合素过表达有关，我们研究了 alpha6beta4 整合素表达是否由于 AR 丧失而导致 AI 前列腺癌报告的冻存耐受性增加。一系列使用 AS（LNCaP LP 和 PC-3 AR）和 AI（LNCaP HP 和 PC-3）细胞系的研究旨在研究导致冷冻反应变化的细胞机制。对 alpha6beta4 整合素表达的研究表明，AI 细胞系过度表达了这种蛋白，从而改变了形态特征并增加了粘附特性。分子研究表明，冷冻后 AI 细胞中 caspase-8、-9 和 -3 的水平显著降低。抑制 alpha6beta4 整合素后，冷冻后 caspase 活性增加（类似于 AS 细胞）并增强细胞死亡。这些数据表明，抑制 alpha6beta4 整合素功能后，AI 细胞在冷冻后表现出更高的易感性。进一步了解雄激素受体相关 alpha6beta4 整合素表达在前列腺癌细胞对冷冻反应中的作用，可能为靶向 AR 信号通路的新型辅助治疗提供新的选择。
