Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
John B. Little Center for Radiation Sciences, Boston, MA, USA.
Oncogene. 2018 Apr;37(16):2150-2164. doi: 10.1038/s41388-017-0117-8. Epub 2018 Jan 26.
Although ΔNp63 is known to promote cancer cell proliferation, the underlying mechanism behind its oncogenic function remains elusive. We report here a functional interplay between ΔNp63 and Δ133p53. These two proteins are co-overexpressed in a subset of human cancers and cooperate to promote cell proliferation. Mechanistically, Δ133p53 binds to ΔNp63 and utilizes its transactivation domain to upregulate GLUT1, GLUT4, and PGM expression driving glycolysis. While increased glycolysis provides cancer cells with anabolic metabolism critical for proliferation and survival, it can be harnessed for selective cancer cell killing. Indeed, we show that tumors overexpressing both ΔNp63 and Δ133p53 exhibit heightened sensitivity to vitamin C that accumulate to a lethal level due to accelerated uptake via overexpressed GLUT1. These observations offer a new therapeutic avenue that could be exploited for clinical applications.
虽然 ΔNp63 已知可促进癌细胞增殖，但它的致癌功能背后的潜在机制仍难以捉摸。我们在这里报告了 ΔNp63 和 Δ133p53 之间的功能相互作用。这两种蛋白质在人类癌症的一部分中共同过表达，并合作促进细胞增殖。在机制上，Δ133p53 与 ΔNp63 结合，并利用其转录激活结构域上调 GLUT1、GLUT4 和 PGM 的表达，从而促进糖酵解。虽然增加的糖酵解为癌细胞提供了增殖和存活所需的合成代谢，但它可以被利用来选择性地杀死癌细胞。事实上，我们发现同时过表达 ΔNp63 和 Δ133p53 的肿瘤对维生素 C 表现出更高的敏感性，由于通过过表达的 GLUT1 加速摄取，维生素 C 积累到致命水平。这些观察结果提供了一个新的治疗途径，可用于临床应用。
