Muthumani Praneetha, Alagarsamy Karthikeyan, Dhandayuthapani Sivanesan, Venkatesan Thiagarajan, Rathinavelu Appu
Rumbaugh Goodwin Institute for Cancer Research, College of Pharmacy, Health Professions Division, Nova Southeastern University, 1850 NW 69th Avenue, Suite #5, Plantation, FL, 33313, USA.
Mol Biol Rep. 2014 Aug;41(8):5533-41. doi: 10.1007/s11033-014-3430-0. Epub 2014 Jun 28.
Hypoxia stimulates several pathways that are critical to cancer cell growth and survival, including activation of vascular endothelial growth factor (VEGF) transcription. Overexpression of VEGF and the extent of neoangiogenesis are closely correlated with tumor development and cancer metastases. Recent studies suggest MDM2 as one of the major regulators of pro-angiogenic mechanisms. To assess the direct correlation of HIF-1α and NF-κB, and the actual mechanism of MDM2 involved in the control over VEGF transcription, we exposed the LNCaP and LNCaP-MST cells (MDM2 transfected) to hypoxia. Our experiments confirm that MDM2 activation can lead to significant decrease in the levels of p53 in MDM2 transfected LNCaP-MST cells than the wild-type LNCaP cells. The results further suggest that MDM2 can be a strong regulator of both p53 dependent and independent transcriptional activity. Similarly, an increased level of other transcription factors such as HIF-1α, P300, STAT3, pAKT and NF-κB was observed. As a point of convergence for many oncogenic signaling pathways, STAT3 is constitutively activated at high frequency in a wide diversity of cancers. Our results indicate that STAT3 can directly regulate VEGF expression that is controlled by MDM2. Furthermore, it is evident from our results that NF-κB may interfere with the transcriptional activity of p53, by downregulating its levels. On the other hand, several pro-angiogenic mechanisms, including VEGF transcription which is controlled by MDM2, seem to be mediated by NF-κB.
缺氧刺激了对癌细胞生长和存活至关重要的多种途径，包括血管内皮生长因子（VEGF）转录的激活。VEGF的过表达和新生血管形成的程度与肿瘤发展和癌症转移密切相关。最近的研究表明MDM2是促血管生成机制的主要调节因子之一。为了评估HIF-1α和NF-κB的直接相关性，以及MDM2参与控制VEGF转录的实际机制，我们将LNCaP和LNCaP-MST细胞（转染了MDM2）暴露于缺氧环境中。我们的实验证实，与野生型LNCaP细胞相比，MDM2激活可导致转染MDM2的LNCaP-MST细胞中p53水平显著降低。结果进一步表明，MDM2可以是p53依赖性和非依赖性转录活性的强调节因子。同样，观察到其他转录因子如HIF-1α、P300、STAT3、pAKT和NF-κB的水平升高。作为许多致癌信号通路的汇聚点，STAT3在多种癌症中高频组成性激活。我们的结果表明，STAT3可以直接调节由MDM2控制的VEGF表达。此外，从我们的结果中可以明显看出，NF-κB可能通过下调p53水平来干扰其转录活性。另一方面，包括由MDM2控制的VEGF转录在内的几种促血管生成机制似乎由NF-κB介导。
