ANKRD22, a novel tumor microenvironment-induced mitochondrial protein promotes metabolic reprogramming of colorectal cancer cells
ANKRD22, a novel tumor microenvironment-induced mitochondrial protein promotes metabolic reprogramming of colorectal cancer cells
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ANKRD22，一种新型肿瘤微环境诱导的线粒体蛋白促进结直肠癌细胞的代谢重编程
DOI：
10.7150/thno.37472
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhu, Yongliang
中科院分区：
文献类型：
--
作者：
Pan, Tianhui;Liu, Jingwen;Zhu, Yongliang
背景：结直肠癌（CRC）预后不良的主要原因是结直肠癌起始细胞（CCIC）的存在。肿瘤微环境（TME）和结直肠癌细胞之间的相互作用诱导重新获得起始细胞的特征，但潜在的机制仍然是难以捉摸的。研究方法：通过CCIC的全局差异cDNA表达谱筛选候选分子，CCIC从患者来源的肿瘤异种移植模型中富集。采用荧光素酶报告基因和染色质免疫沉淀法研究TME因子对ANKRD 22转录的调控机制。通过细胞外通量和基于13 C的代谢通量分析来监测含锚蛋白重复结构域蛋白22（ANKRD 22）对能量代谢的影响。使用质谱法鉴定ANKRD 22的相互作用伴侣。电镜观察ANKRD 22过表达CCIC的形态学变化。脂质组学分析ANKRD 22对线粒体脂质代谢的影响。结果：我们鉴定了一种新的核编码线粒体膜蛋白ANKRD 22，其在CCIC中上调。我们发现ANKRD 22是由不同TME刺激激活的p38/MAX通路诱导的。MAX作为一个关键转录因子，促进ANKRD 22的转录。ANKRD 22的表达促进了糖酵解，并降低了ATP/ADP和增加了AMP/ATP水平，这与其与丙酮酸脱氢酶激酶亚型1（PDK 1）和ATP合成酶的多个亚基的相互作用有关。此外，在CCIC中，ANKRD 22与脂质转运蛋白Extended Synaptotagmin-1（E-Syt 1）合作，将多余的脂质转运到线粒体中，并以不依赖自噬的方式减少线粒体的数量，从而满足CCIC的代谢要求。结论：TME诱导的ANKRD 22可促进结直肠癌细胞的代谢重编程。我们的研究已经确定ANKRD 22/E-Syt 1作为根除CCIC的潜在靶点。
Background: The leading cause of poor prognosis in colorectal cancer (CRC) is the presence of colorectal cancer-initiating cells (CCICs). The interplay between the tumor microenvironment (TME) and CRC cells induces reacquisition of initiating cell characteristics, but the underlying mechanisms remain elusive. Methods: Candidate molecules were screened by global differential cDNA expression profiles of CCICs, which were enriched from patient-derived tumor xenograft models. Luciferase reporters and chromatin immunoprecipitation assays were used to explore the mechanism of TME factors regulating the transcription of ANKRD22. The effects of Ankyrin repeat domain-containing protein 22 (ANKRD22) on energy metabolism were monitored by extracellular flux and 13C-based metabolic flux analysis. Mass spectrometry was used to identify the interacting partners of ANKRD22. Morphological changes of CCICs overexpressing ANKRD22 were observed by electron microscopy. The effects of ANKRD22 on mitochondrial lipid metabolism were analyzed by lipidomics. Results: We identified a novel nucleus-encoded mitochondrial membrane protein, ANKRD22, which was upregulated in CCICs. We found that ANKRD22 was induced by the p38/MAX pathway activated by different TME stimuli. As a key transcription factor, MAX promoted the transcription of ANKRD22. Expression of ANKRD22 promoted glycolysis associated with a decrease in ATP/ADP and an increase in AMP/ATP levels, which were related to its interaction with pyruvate dehydrogenase kinase isoform 1 (PDK1) and multiple subunits of ATP synthase. Further, in CCICs, ANKRD22 cooperated with the lipid transport protein, Extended Synaptotagmin-1 (E-Syt1), to transport excess lipids into mitochondria and reduced the number of mitochondria in an autophagy-independent manner, thus meeting the metabolic requirements of CCICs. Conclusion: ANKRD22 induced by TME promotes the metabolic reprogramming of CRC cells. Our study has identified ANKRD22/E-Syt1 as a potential target for eradicating CCICs.