Background The p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and p53 and thus, acts as an oncogene. Results By employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch. Finally, PpIX showed potent antitumor effect and inhibited the growth of xenograft human tumors in mice. Conclusion Our findings may in future contribute to the successful repurposing of PpIX into clinical practice.

中文翻译：

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原卟啉 IX（一种氨基乙酰丙酸的代谢物）重新激活 TAp73 肿瘤抑制因子可诱导 TP53 缺陷型癌细胞凋亡。

背景 p73 蛋白是一种肿瘤抑制因子，与 p53 具有结构和功能相似性。p73 以两种主要的亚型表达；TA 亚型与 p53 通路相互作用，因此充当肿瘤抑制因子，而 N 端截短的 ΔN 亚型抑制 TAp73 和 p53，因此充当癌基因。结果通过采用药物再利用方法，我们发现原卟啉 IX (PpIX) 是一种氨基乙酰丙酸的代谢物，用于癌症的光动力治疗，可稳定 TAp73 并激活缺乏 p53 的癌细胞中的 TAp73 依赖性细胞凋亡。TAp73 激活的机制是通过破坏 TAp73/MDM2 和 TAp73/MDMX 相互作用以及通过泛素连接酶 Itch 抑制 TAp73 降解。最后，PpIX 显示出有效的抗肿瘤作用并抑制小鼠异种移植人肿瘤的生长。