Simonnet Hélène, Alazard Nathalie, Pfeiffer Kathy, Gallou Catherine, Béroud Christophe, Demont Jocelyne, Bouvier Raymonde, Schägger Hermann, Godinot Catherine
CGMC (Center of Molecular and Cell Genetics), Unit 5534 of the CNRS and of the University Lyon 1-Claude Bernard, Villeurbanne, France.
Carcinogenesis. 2002 May;23(5):759-68. doi: 10.1093/carcin/23.5.759.
A mechanism decreasing oxidative metabolism during normal cell division and growth is expected to direct substrates toward biosyntheses rather than toward complete oxidation to CO(2). Hence, any event decreasing oxidative phosphorylations (OXPHOS) could provide a proliferating advantage to a transformed or tumor cell in an oxidative tissue. To test this hypothesis, we studied mitochondrial enzymes, DNA and OXPHOS protein content in three types of renal tumors from 25 patients. Renal cell carcinomas (RCCs) of clear cell type (CCRCCs) originate from the proximal tubule and are most aggressive. Chromophilic RCCs, from similar proximal origin, are less aggressive. The benign renal oncocytomas originate from collecting duct cells. Mitochondrial enzyme and DNA contents in all tumor types or grades differed significantly from normal tissue. Mitochondrial impairment increased from the less aggressive to the most aggressive RCCs, and correlated with a considerably decreased content of OXPHOS complexes (complexes II, III, and IV of the respiratory chain, and ATPase/ATP synthase) rather than to the mitochondrial content (citrate synthase and mitochondrial (mt)DNA). In benign oncocytoma, some mitochondrial parameters (mtDNA, citrate synthase, and complex IV) were increased 4- to 7-fold, and some were slightly increased by a factor of 2 (complex V) or close to normal (complexes II and III). A low content of complex V protein was found in all CCRCC and chromophilic tumors studied. However F(1)-ATPase activity was not consistently decreased and its impairment was associated with increased aggressiveness in CCRCCs. Immunodetection of free F(1)-sector of complex V demonstrated a disturbed assembly/stability of complex V in several CCRCC and chromophilic tumors. All results are in agreement with the hypothesis that a decreased OXPHOS capacity favors faster growth or increased invasiveness.
在正常细胞分裂和生长过程中，一种降低氧化代谢的机制有望将底物导向生物合成，而非完全氧化为二氧化碳。因此，任何降低氧化磷酸化（OXPHOS）的事件都可能为氧化组织中的转化细胞或肿瘤细胞提供增殖优势。为了验证这一假设，我们研究了25例患者的三种肾肿瘤中的线粒体酶、DNA和OXPHOS蛋白含量。透明细胞型肾细胞癌（CCRCC）起源于近端小管，侵袭性最强。嗜色性肾细胞癌起源于相似的近端部位，侵袭性较弱。良性肾嗜酸细胞瘤起源于集合管细胞。所有肿瘤类型或分级中的线粒体酶和DNA含量与正常组织均有显著差异。线粒体损伤程度从侵袭性较弱的肾细胞癌到侵袭性最强的肾细胞癌逐渐增加，且与OXPHOS复合物（呼吸链的复合物II、III和IV以及ATP酶/ATP合酶）含量的显著降低相关，而非与线粒体含量（柠檬酸合酶和线粒体（mt）DNA）相关。在良性嗜酸细胞瘤中，一些线粒体参数（mtDNA、柠檬酸合酶和复合物IV）增加了4至7倍，一些略有增加（复合物V增加了2倍）或接近正常（复合物II和III）。在所有研究的CCRCC和嗜色性肿瘤中均发现复合物V蛋白含量较低。然而，F1-ATP酶活性并非始终降低，其损伤与CCRCC的侵袭性增加有关。复合物V游离F1亚基的免疫检测表明，在一些CCRCC和嗜色性肿瘤中，复合物V的组装/稳定性受到干扰。所有结果均与以下假设一致：OXPHOS能力降低有利于更快生长或增加侵袭性。
