Koido Masaru, Haga Naomi, Furuno Aki, Tsukahara Satomi, Sakurai Junko, Tani Yuri, Sato Shigeo, Tomida Akihiro
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Oncotarget. 2017 Feb 14;8(7):11841-11854. doi: 10.18632/oncotarget.14415.
Mitochondria can be involved in regulating cellular stress response to hypoxia and tumor growth, but little is known about that mechanistic relationship. Here, we show that mitochondrial deficiency severely retards tumor xenograft growth with impairing hypoxic induction of HIF-1 transcriptional activity. Using mtDNA-deficient ρ0 cells, we found that HIF-1 pathway activation was comparable in slow-growing ρ0 xenografts and rapid-growing parental xenografts. Interestingly, we found that ex vivo ρ0 cells derived from ρ0 xenografts exhibited slightly increased HIF-1α expression and modest HIF-1 pathway activation regardless of oxygen concentration. Surprisingly, ρ0 cells, as well as parental cells treated with oxidative phosphorylation inhibitors, were unable to boost HIF-1 transcriptional activity during hypoxia, although HIF-1α protein levels were ordinarily increased in these cells under hypoxic conditions. These findings indicate that mitochondrial deficiency causes loss of hypoxia-induced HIF-1 transcriptional activity and thereby might lead to a constitutive HIF-1 pathway activation as a cellular adaptation mechanism in tumor microenvironment.
线粒体可能参与调节细胞对缺氧的应激反应以及肿瘤生长，但对这种机制关系了解甚少。在此，我们表明线粒体缺陷严重阻碍肿瘤异种移植生长，并损害缺氧诱导的HIF-1转录活性。使用线粒体DNA缺陷的ρ0细胞，我们发现HIF-1通路激活在生长缓慢的ρ0异种移植和快速生长的亲代异种移植中相当。有趣的是，我们发现源自ρ0异种移植的离体ρ0细胞无论氧浓度如何，HIF-1α表达均略有增加且HIF-1通路有适度激活。令人惊讶的是，ρ0细胞以及用氧化磷酸化抑制剂处理的亲代细胞在缺氧期间无法增强HIF-1转录活性，尽管在缺氧条件下这些细胞中HIF-1α蛋白水平通常会增加。这些发现表明线粒体缺陷导致缺氧诱导的HIF-1转录活性丧失，从而可能导致HIF-1通路作为肿瘤微环境中的一种细胞适应机制而发生组成性激活。
