PDF(Pubmed)
Abstract：
Among the main metabolic pathways implicated in cancer cell proliferation are those of cholesterol and fatty acid synthesis, both of which are tightly regulated by sterol regulatory element-binding proteins (SREBPs). SREBPs are activated through specific cleavage by membrane-bound transcription factor protease 1 (MBTPS1), a serine protease that cleaves additional substrates (ATF6, BDNF, CREBs and somatostatin), some of which are also implicated in cell proliferation. The goal of this study was to determine whether MBTPS1 may serve as a master regulator in proliferation of colorectal cancer (CRC). Tumors from CRC patients showed variable levels of MBTPS1 mRNA, which were in positive correlation with the levels of SREBPs and ATF6, and in reverse correlation with BDNF levels. Chemical inhibition of MBTPS1 activity in two CRC-derived cell lines resulted in a marked decrease in the levels of SREBPs, but not of its other substrates and a marked decrease in cell proliferation, which suggested that MBTPS1 activity is critical for proliferation of these cells. In accordance, CRISPR/Cas9 targeted knockout (KO) of the MBTPS1 gene resulted in the survival of only a single clone that presented a phenotype of severely attenuated proliferation and marked downregulation of several energy metabolism pathways. We further showed that survival of the MBTPS1 KO clone was dependent upon significant upregulation of the type-1 interferon pathway, the inhibition of which halted proliferation entirely. Finally, rescue of the MBTPS1 KO cells, resulted in partial restoration of MBTPS1 levels, which was in accordance with partial recovery in proliferation and in SREBP levels. These finding suggest that MBTPS1 plays a critical role in regulating colon cancer proliferation primarily through SREBP-associated lipid metabolism, and as such may serve as a possible therapeutic target in CRC.
摘要：
与癌细胞增殖有关的主要代谢途径是胆固醇和脂肪酸合成，两者都受到固醇调节元件结合蛋白（SREBPs）的严格调节。SREBPs通过膜结合转录因子蛋白酶1（MBTPS1）的特异性切割被激活，一种切割额外底物的丝氨酸蛋白酶(ATF6，BDNF，CREB和生长抑素），其中一些也与细胞增殖有关。这项研究的目的是确定MBTPS1是否可以作为大肠癌（CRC）增殖的主要调节因子。来自CRC患者的肿瘤显示不同水平的MBTPS1mRNA，与SREBPs和ATF6水平呈正相关，与BDNF水平呈负相关。化学抑制两种CRC衍生细胞系中的MBTPS1活性导致SREBP水平显着降低，但不是它的其他底物和细胞增殖的显著减少，这表明MBTPS1活性对于这些细胞的增殖至关重要。InAccording,MBTPS1基因的CRISPR/Cas9靶向敲除（KO）仅导致单个克隆的存活，该克隆呈现严重减弱的增殖和几种能量代谢途径的显着下调的表型。我们进一步表明，MBTPS1KO克隆的存活依赖于1型干扰素途径的显著上调，其抑制作用完全停止了增殖。最后,拯救MBTPS1KO细胞，导致MBTPS1水平的部分恢复，这与增殖和SREBP水平的部分恢复一致。这些发现表明，MBTPS1主要通过SREBP相关的脂质代谢在调节结肠癌增殖中起关键作用。因此可以作为CRC中可能的治疗靶标。
