HIF-1α activation under glucose deprivation plays a central role in the acquisition of anti-apoptosis in human colon cancer cells
HIF-1α activation under glucose deprivation plays a central role in the acquisition of anti-apoptosis in human colon cancer cells
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DOI：
10.3892/ijo.2014.2367
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发表时间：
2014-06-01
影响因子：
5.2
通讯作者：
Hamano, Kimikazu
中科院分区：
文献类型：
--
作者：
Nishimoto, Arata;Kugimiya, Naruji;Hamano, Kimikazu
肿瘤块中血管网络发育不良导致氧气和营养供应不良。为了适应缺氧微环境，众所周知，癌细胞激活转录因子缺氧诱导因子-1 α（HIP-1 α）。HIF-1 α在缺氧诱导的代谢转换、抗凋亡、血管生成和耐药性中起着重要作用。葡萄糖剥夺，另一个主要的应激微环境，保护癌细胞免受药物诱导的凋亡。然而，癌细胞适应不良营养条件的分子机制仍然知之甚少。在本研究中，我们重点关注HIF-1 α、信号转导和转录激活因子3（STAT 3）和转录因子4（TCF 4），它们参与细胞存活、抗凋亡和耐药性。我们研究了这些转录因子在葡萄糖剥夺下的活性以及它们之间的关系。我们的研究结果表明，葡萄糖剥夺增加HIF-1 α，STAT 3和TCF 4 DNA结合活性，以及其靶基因OCT 4，BCL-2和VEGF的表达水平。在葡萄糖剥夺下，HIF-1 α敲低显著增加聚（ADP-核糖）聚合酶1（PARP-1）的裂解，其水平高于STAT 3敲低。此外，HIP-1 α敲低导致STAT 3和TCF 4的表达水平显著降低，尽管STAT 3敲低仅降低HIF-1 α表达水平。我们的数据表明，在葡萄糖剥夺下HIF-1 α信号通路的激活导致人类结肠癌细胞获得抗凋亡特性，靶向HIP-1 α信号通路可能为治疗对常规疗法耐药的癌症提供有效途径。
A poor vascular network development in a tumor mass leads to poor oxygen and nutrient supply. To adapt to a hypoxic microenvironment, it is well-known that cancer cells activate the transcription factor hypoxia-inducible factor-1 alpha (HIP-1 alpha). HIF-1 alpha plays a central role in hypoxia-induced metabolic switching, anti-apoptosis, angiogenesis and drug resistance. Glucose deprivation, another major stressful microenvironment, protects cancer cells from drug-induced apoptosis. However, the molecular mechanisms by which cancer cells adapt to poor nutrient conditions remain poorly understood. In this study, we focused on HIF-1 alpha, signal transducer and activator of transcription 3 (STAT3) and transcription factor 4 (TCF4), which are involved in cell survival, anti-apoptosis and drug resistance. We examined their activities and the relationships among these transcription factors under glucose deprivation. Our results showed that glucose deprivation increased HIF-1 alpha, STAT3 and TCF4 DNA-binding activity, as well as the expression levels of their target genes OCT4, BCL-2 and VEGF. HIF-1 alpha knockdown significantly increased poly(ADP-ribose) polymerase 1 (PARP-1) cleavage at higher levels than STAT3 knockdown under glucose deprivation. Furthermore, HIP-1 alpha knockdown led to a significant decrease in the expression levels of both STAT3 and TCF4, although STAT3 knockdown decreased only HIF-1 alpha expression level. Our data indicated that activation of the HIF-1 alpha signaling pathway under glucose deprivation leads to the acquisition of anti-apoptotic properties in human colon cancer cells, and targeting the HIP-1 alpha signaling pathway may provide an effective avenue for treating cancers resistant to conventional therapy.