Human serum albumin (HSA) fusion protein is a viable and effective approach to target and inhibit essential intracellular pathways. It has previously been shown that an HSA fusion protein containing a p53-reactivating peptide (rHSA-p53i) retains the binding activity to MDM2 and MDMX, resulting in p53 transcription-dependent apoptosis. Here, we demonstrate that rHSA-p53i is able to bind and neutralize anti-apoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1. This interaction displaces pro-apoptotic Bak and subsequently leads to intrinsic apoptosis via mimicking a p53 transcription-independent pathway. Cytotoxicity induced by rHSA-p53i, via p53 transcription dependent and independent apoptotic pathways, is irrespective of the p53 status in MDA-MB-231, HeLa, and SJSA-1 cells possessing either mutant, deficient, or wild-type p53. The therapeutic potential is also confirmed by treating SJSA-1 and MDA-MB-231 xenograft mouse tumors with rHSA-p53i. These data reveal that rHSA-p53i interferes with at least four intracellular targets, making it a viable therapeutic protein for the treatment of a variety of cancers, as well as a carrier to deliver fatty acid-modified chemotherapeutics.

中文翻译：

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人血清白蛋白和p53衍生的肽融合蛋白可促进细胞毒性，而与癌细胞中p53的状态无关

人血清白蛋白（HSA）融合蛋白是靶向和抑制基本细胞内途径的可行且有效的方法。先前已显示，含有p53活化肽（rHSA-p53i）的HSA融合蛋白保留了与MDM2和MDMX的结合活性，从而导致了p53转录依赖性细胞凋亡。在这里，我们证明了rHSA-p53i能够结合并中和抗凋亡的Bcl-2家族蛋白Bcl-xL和Mcl-1。这种相互作用取代了促凋亡的Bak，随后通过模仿p53转录独立途径导致内在凋亡。无论是否具有突变型，缺陷型或野生型p53的MDA-MB-231，HeLa和SJSA-1细胞中的p53状态，rHSA-p53i通过p53转录依赖性和独立的凋亡途径诱导的细胞毒性。通过用rHSA-p53i治疗SJSA-1和MDA-MB-231异种移植小鼠肿瘤也证实了治疗潜力。这些数据表明，rHSA-p53i干扰至少四个细胞内靶标，使其成为治疗多种癌症的可行治疗蛋白，以及传递脂肪酸修饰的化学治疗剂的载体。