Emerging data indicate that the reverse transcriptase (RT) protein encoded by LINE-1 transposable elements is a promising cancer target. Nonnucleoside RT inhibitors, e.g. efavirenz (EFV) and SPV122.2, reduce proliferation and promote differentiation of cancer cells, concomitant with a global reprogramming of the transcription profile. Both inhibitors have therapeutic anticancer efficacy in animal models. Here we have sought to clarify the mechanisms of RT inhibitors in cancer cells. We report that exposure of PC3 metastatic prostate carcinoma cells to both RT inhibitors results in decreased proliferation and concomitantly induces genome damage, associated with rearrangements of the nuclear architecture, particularly at peripheral chromatin, with disruption of the nuclear lamina and budding of micronuclei. These changes are reversible upon discontinuation of the RT-inhibitory treatment, with reconsititution of the lamina and resumption of the cancer cell original features. The use of pharmacological autophagy inhibitors proves that autophagy is largely responsible for the antiproliferative effect of RT inhibitors. These alterations are not induced in non-cancer cell lines exposed to RT inhibitors. These data provide novel insight in the molecular pathways targeted by RT inhibitors in cancer cells.

中文翻译：

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逆转录酶抑制剂促进前列腺癌细胞核结构的重塑并诱导自噬。

新兴数据表明，LINE-1转座因子编码的逆转录酶（RT）蛋白是有希望的癌症靶标。非核苷RT抑制剂，例如依非韦伦（efavirenz，EFV）和SPV122.2，可降低增殖并促进癌细胞的分化，并伴随着转录谱的整体重编程。两种抑制剂在动物模型中均具有治疗性抗癌功效。在这里，我们试图阐明RT抑制剂在癌细胞中的机制。我们报告说，将PC3转移性前列腺癌细胞暴露于两种RT抑制剂会导致增殖减少，并同时诱导基因组损伤，与核结构的重排有关，特别是在外周染色质上，核层板的破坏和微核的萌芽。这些改变在RT抑制治疗的中断，薄片的重新构成和癌细胞原始特征的恢复后是可逆的。药理自噬抑制剂的使用证明自噬是RT抑制剂抗增殖作用的主要原因。在暴露于RT抑制剂的非癌细胞系中不会诱导这些改变。这些数据为RT抑制剂在癌细胞中靶向的分子途径提供了新颖的见解。