Sünderhauf Annika, Raschdorf Annika, Hicken Maren, Schlichting Heidi, Fetzer Franziska, Brethack Ann-Kathrin, Perner Sven, Kemper Claudia, Ghebrehiwet Berhane, Sina Christian, Derer Stefanie
Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany.
Institute of Pathology, University Hospital Schleswig-Holstein, Lübeck, Germany.
Front Oncol. 2020 Sep 30;10:575854. doi: 10.3389/fonc.2020.575854. eCollection 2020.
Self-sustained cell proliferation constitutes one hallmark of cancer enabled by aerobic glycolysis which is characterized by imbalanced glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) activity, named the Warburg effect. The C1q binding protein (; gC1qR) is pivotal for mitochondrial protein translation and thus OXPHOS activity. Due to its fundamental role in balancing OXPHOS and glycolysis, mice display embryonic lethality, while gC1qR is excessively up-regulated in cancer. Although gC1qR encompasses an -terminal mitochondrial leader it is also located in other cellular compartments. Hence, we aimed to investigate mechanisms regulating gC1qR cellular localization and its impact on tumor cell metabolism. We identified two caspase-1 cleavage sites in human gC1qR. GC1qR cleavage by active caspase-1 was unraveled as a cellular mechanism that prevents mitochondrial gC1qR import, thereby enabling aerobic glycolysis and enhanced cell proliferation. , tumor grading correlated with non-mitochondrial-located gC1qR as well as with caspase-1 activation in colorectal carcinoma patients. Together, active caspase-1 cleaves gC1qR and boosts aerobic glycolysis in tumor cells.
细胞的自我维持增殖是癌症的一个标志，这一过程由有氧糖酵解驱动，其特征是糖酵解和线粒体氧化磷酸化（OXPHOS）活性失衡，即所谓的瓦伯格效应。C1q结合蛋白（；gC1qR）对线粒体蛋白质翻译至关重要，因此对OXPHOS活性也至关重要。由于其在平衡OXPHOS和糖酵解中的基本作用， 小鼠表现出胚胎致死性，而gC1qR在癌症中过度上调。尽管gC1qR包含一个N端线粒体前导序列，但它也位于其他细胞区室中。因此，我们旨在研究调节gC1qR细胞定位的机制及其对肿瘤细胞代谢的影响。我们在人gC1qR中鉴定出两个半胱天冬酶-1切割位点。活性半胱天冬酶-1对GC1qR的切割被揭示为一种细胞机制，可阻止线粒体gC1qR的导入，从而实现有氧糖酵解并增强细胞增殖。 ，在结直肠癌患者中，肿瘤分级与非线粒体定位的gC1qR以及半胱天冬酶-1激活相关。总之，活性半胱天冬酶-1切割gC1qR并促进肿瘤细胞中的有氧糖酵解。
