Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis
Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis
复制标题
DOI：
10.1038/sj.onc.1203814
复制
发表时间：
2000-09-21
期刊：
影响因子：
8
通讯作者：
Kim, KW
中科院分区：
文献类型：
--
作者：
Baek, JH;Jang, JE;Kim, KW
低氧和营养消耗在肿瘤发生中发挥着关键作用，但人们对它们如何相互作用以产生肿瘤存活和肿瘤恶性肿瘤知之甚少。在本研究中，我们研究了缺氧调节血清剥夺的HepG2细胞凋亡的机制，结果表明缺氧阻断了细胞凋亡，并伴随着Bax/Bcl-2比值降低、细胞色素c释放抑制和caspase-3活性降低。更重要的是，在缺氧/血清剥夺条件下，VEGF 及其受体 2 (KDR) 表达增加，表明 VEGF 可能以自我促进的方式充当生存因子。重组人 VEGF (rhVEGF) 抑制血清剥夺诱导的细胞凋亡，抗 VEGF 中和抗体阻断缺氧的抗凋亡活性，此外，受体酪氨酸激酶抑制剂阻断缺氧的抗凋亡活性。我们的研究进一步表明，rhVEGF 或缺氧诱导血清剥夺细胞中的 ERK 磷酸化，而 MAPK/ERK 的特异性抑制剂 PD98059 消除了rhVEGF 或缺氧通过增加 Bax/Bcl-2 比率和 caspase-3 活性来实现。我们的数据使我们得出结论，rhVEGF 诱导 ERK 磷酸化和 Bax/Bcl-2 比率降低意味着缺氧诱导的 VEGF 通过激活 MAPK/ERK 途径来防止血清剥夺细胞的凋亡。综上所述，我们认为缺氧通过降低细胞凋亡的易感性来提高营养耗尽的肿瘤细胞的存活率，从而导致肿瘤恶性肿瘤。
Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumor malignancy. In the present study, we investigated the mechanism underlying hypoxia-modulated apoptosis of serum-deprived HepG2 cells, Our results showed that hypoxia blocked the apoptosis, which was accompanied with decreased Bax/ Bcl-2 ratio, inhibited cytochrome c release, and reduced caspase-3 activity. More importantly, increased expressions of VEGF and its receptor-2 (KDR) under hypoxic/ serum-deprived condition suggest that VEGF may act as a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum deprivation-induced apoptosis, and anti-VEGF neutralizing antibody block anti-apoptotic activity of hypoxia, In addition, inhibitors of receptor tyrosine kinase blocked anti-apoptosis of hypoxia, Our study further showed that rhVEGF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a specific inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic activity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 activity. Our data led us to conclude that induction of ERK phosphorylation and decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxia-induced VEGF prevents apoptosis of serum-deprived cells by activating the MAPK/ERK pathway. Taken together, we propose that hypoxia enhances survival of nutrient-depleted tumor cells by reducing susceptibility to apoptosis, which consequently leads to tumor malignancy.