School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
Pharmacol Res. 2015 Mar;93:36-42. doi: 10.1016/j.phrs.2014.12.006. Epub 2015 Jan 9.
Chemotherapy targeting anti-angiogenesis in tumors may have insufficient efficacy, but little is known about the underlying mechanisms. Here, we showed that the Ca(2+)-permeable channel, TrpC5, is highly expressed in human breast cancer after long-term chemotherapy drug-treatment. It mediates downstream hypoxia-inducible factor 1α accumulation in the nucleus, and then activates the transcription of vascular endothelial growth factor which promotes tumor angiogenesis, leading to a poor chemotherapeutic outcome. We verified this mechanism at both the cellular and xenograft levels. Moreover, in samples from patients, high TrpC5 expression was correlated with enhanced tumor vasculature after chemotherapy. Taken together, our research demonstrated the essential role of TrpC5 in tumor angiogenesis when facing the challenge of chemotherapy and presents a new potential target for overcoming the high vasculature of human breast cancer after chemotherapy.
靶向肿瘤抗血管生成的化疗可能疗效不足，但对其潜在机制知之甚少。在这里，我们发现，在长期化疗药物治疗后，钙渗透性通道 TrpC5 在人乳腺癌中高度表达。它介导下游低氧诱导因子 1α 在核内的积累，然后激活血管内皮生长因子的转录，促进肿瘤血管生成，导致化疗效果不佳。我们在细胞和异种移植水平上验证了这一机制。此外，在患者样本中，TrpC5 表达升高与化疗后肿瘤血管增强相关。总之，我们的研究表明，TrpC5 在肿瘤血管生成中具有重要作用，这为应对化疗的挑战提供了一个新的潜在靶点，并为克服化疗后人类乳腺癌的高血管生成提供了新的靶点。
