Hypoxia activates the K-ras proto-oncogene to stimulate angiogenesis and inhibit apoptosis in colon cancer cells.
Hypoxia activates the K-ras proto-oncogene to stimulate angiogenesis and inhibit apoptosis in colon cancer cells.
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DOI：
10.1371/journal.pone.0010966
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发表时间：
2010-06-04
期刊：
影响因子：
3.7
通讯作者：
Chung DC
中科院分区：
文献类型：
--
作者：
Zeng M;Kikuchi H;Pino MS;Chung DC
KRAS 原癌基因在许多人类肿瘤的发展中发挥着关键作用，通常由体细胞突变或通过特定生长因子受体的信号传导激活。然而，微环境与 K-ras 活性之间的相互作用尚未明确。当肿瘤生长超过氧气供应时，就会不可避免地出现缺氧。发生一系列精心策划的细胞适应，刺激血管生成并提高肿瘤在缺氧条件下的存活率。我们之前的研究表明，突变的 KRAS 等位基因可以与缺氧相互作用，诱导结肠癌中血管内皮生长因子（VEGF）的产生。我们试图确定类似的缺氧反应是否也存在于没有 KRAS 突变的肿瘤中。缺氧持续增加具有野生型 KRAS 基因的结肠癌细胞系中活化的 GTP 结合 K-ras 的水平，这取决于 c-Src 的激活。通过 PP2 处理或 siRNA 敲低来抑制 c-Src 可阻断 K-ras 的缺氧激活。 K-ras 的这种激活不依赖于 EGFR，并导致 Akt 磷酸化和诱导 VEGF 表达。此外，K-ras 的激活显着阻止缺氧条件下的细胞凋亡。这些研究揭示了一种独特的缺氧适应机制，该机制在缺乏突变 KRAS 癌基因的情况下激活 K-ras 信号传导。
The KRAS proto-oncogene plays a key role in the development of many human tumors and is commonly activated by somatic mutation or signaling through specific growth factor receptors. However, the interaction between the micro-environment and K-ras activity has not been defined. Hypoxia invariably develops as tumors outgrow their supply of oxygen. A series of well-orchestrated cellular adaptations occur that stimulate angiogenesis and enhance survival of the tumor in hypoxic conditions. Our previous studies demonstrated that mutant KRAS alleles can interact with hypoxia to induce vascular endothelial growth factor (VEGF) in colon cancer. We sought to determine whether similar hypoxic responses are also present in tumors without a KRAS mutation. Hypoxia consistently increased the levels of activated, GTP-bound K-ras in colon cancer cell lines with a wild-type KRAS gene, and this depended upon the activation of c-Src. Inhibition of c-Src by PP2 treatment or siRNA knockdown blocked the hypoxic activation of K-ras. This activation of K-ras did not depend upon EGFR and resulted in the phosphorylation of Akt and induction of VEGF expression. In addition, activation of K-ras significantly blocked apoptosis in hypoxic conditions. These studies reveal a unique adaptive mechanism in hypoxia that activates K-ras signaling in the absence of a mutant KRAS oncogene.
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