Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
J Pathol. 2012 Feb;226(3):482-94. doi: 10.1002/path.2998. Epub 2011 Oct 19.
Chromosomal instability (CIN) has been implicated in multidrug resistance and the silencing of the ceramide transporter, CERT, promotes sensitization to diverse cytotoxics. An improved understanding of mechanisms governing multidrug sensitization might provide insight into pathways contributing to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CERT-specific multidrug sensitization is associated with enhanced autophagosome-lysosome flux, resulting from the expression of LAMP2 following CERT silencing in colorectal and HER2(+) breast cancer cell lines. Live cell microscopy analysis revealed that CERT depletion induces LAMP2-dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CERT is relatively over-expressed in HER2(+) breast cancer and CERT protein expression acts as an independent prognostic variable and predictor of outcome in adjuvant chemotherapy-treated patients with primary breast cancer. These data suggest that the induction of LAMP2-dependent autophagic flux through CERT targeting may provide a rational approach to enhance multidrug sensitization and potentiate the death of polyploid cells following paclitaxel exposure to limit the acquisition of CIN and intra-tumour heterogeneity.
染色体不稳定性 (CIN) 与多药耐药有关，而神经酰胺转运蛋白 CERT 的沉默则促进了对多种细胞毒素的敏感性。对多药敏感机制的深入了解可能有助于深入了解导致 CIN 癌细胞死亡的途径。我们采用综合功能基因组学方法发现，CERT 特异性多药敏感与增强的自噬体溶酶体流有关，这是由于在结直肠和 HER2(+)乳腺癌细胞系中沉默 CERT 后表达 LAMP2 所致。活细胞显微镜分析显示，在紫杉醇存在的情况下，CERT 耗竭诱导有丝分裂后多倍体细胞依赖 LAMP2 的死亡。我们发现 CERT 在 HER2(+)乳腺癌中相对过表达，CERT 蛋白表达作为独立的预后变量和原发性乳腺癌接受辅助化疗治疗患者的结局预测因子。这些数据表明，通过 CERT 靶向诱导 LAMP2 依赖性自噬流可能为增强多药敏感性和增强紫杉醇暴露后多倍体细胞的死亡提供一种合理的方法，以限制 CIN 的获得和肿瘤内异质性。
