Kannen Vinicius, Garcia Sergio Britto, Silva Wilson A, Gasser Martin, Mönch Romana, Alho Eduardo Joaquim Lopes, Heinsen Helmut, Scholz Claus-Jürgen, Friedrich Mike, Heinze Katrin Gertrud, Waaga-Gasser Ana Maria, Stopper Helga
Department of Toxicology, University of Wuerzburg, Germany.
Department of Pathology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Cell Signal. 2015 Sep;27(9):1781-8. doi: 10.1016/j.cellsig.2015.05.008. Epub 2015 May 22.
Colon cancer is one of the most common tumors in the human population. Recent studies have shown a reduced risk for colon cancer in patients given the antidepressant fluoxetine (FLX). The exact mechanism by which FLX might protect from colon cancer remains however controversial. Here, FLX reduced the development of different colon tumor xenografts, as well as proliferation in hypoxic tumor areas within them. FLX treatment also decreased microvessel numbers in tumors. Although FLX did not increase serum and tumor glucose levels as much as the colon chemotherapy gold standard Fluorouracil did, lactate levels were significantly augmented within tumors by FLX treatment. The gene expression of the MCT4 lactate transporter was significantly downregulated. Total protein amounts from the third and fifth mitochondrial complexes were significantly decreased by FLX in tumors. Cell culture experiments revealed that FLX reduced the mitochondrial membrane potential significantly and disabled the reactive oxygen species production of the third mitochondrial complex. Furthermore, FLX arrested hypoxic colon tumor cells in the G0/G1 phase of the cell-cycle. The expression of key cell-cycle-related checkpoint proteins was enhanced in cell culture and in vivo experiments. Therefore, we suggest FLX impairs energy generation, cell cycle progression and proliferation in tumor cells, especially under condition of hypoxia. This then leads to reduced microvessel formation and tumor shrinkage in xenograft models.
结肠癌是人类最常见的肿瘤之一。最近的研究表明，服用抗抑郁药氟西汀（FLX）的患者患结肠癌的风险降低。然而，FLX预防结肠癌的确切机制仍存在争议。在此，FLX减少了不同结肠肿瘤异种移植瘤的生长，以及其中缺氧肿瘤区域的增殖。FLX治疗还减少了肿瘤中的微血管数量。虽然FLX不像结肠化疗金标准氟尿嘧啶那样大幅提高血清和肿瘤葡萄糖水平，但FLX治疗显著提高了肿瘤内的乳酸水平。MCT4乳酸转运蛋白的基因表达显著下调。肿瘤中，FLX使第三和第五线粒体复合物的总蛋白量显著降低。细胞培养实验表明，FLX显著降低线粒体膜电位，并抑制第三线粒体复合物的活性氧生成。此外，FLX使缺氧结肠肿瘤细胞停滞在细胞周期的G0/G1期。在细胞培养和体内实验中，关键细胞周期相关检查点蛋白的表达增强。因此，我们认为FLX损害肿瘤细胞的能量生成、细胞周期进程和增殖，尤其是在缺氧条件下。这进而导致异种移植模型中微血管形成减少和肿瘤缩小。
