LBPO.MCB01 · 分子与细胞生物学 · Late-Breaking
靶向PIP4K2A的多肽：PTEN缺陷型癌症的一种新型治疗策略
Peptides targeting PIP4K2A : A novel therapeutic strategy for PTEN-deficient cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肿瘤抑制基因通过抑制失控的细胞增殖对维持正常细胞发育至关重要，其失活是癌症进展的标志。基于多肽的疗法因其高靶点特异性、生物活性和良好的安全性而成为一种有前景的治疗方式。在肿瘤抑制因子中，磷酸酶和张力蛋白同源物（PTEN）的异常常源于基因缺失、异常DNA甲基化或功能性蛋白表达丧失。PTEN缺陷见于约20-30%的人类癌症，并与侵袭性肿瘤行为密切相关。我们之前的研究发现，磷脂酰肌醇-5-磷酸4-激酶2型α（PIP4K2A）已被确定为PTEN缺陷型癌症中肿瘤进展的负调控因子。然而，靶向PIP4K2A通路的基于多肽的治疗策略尚未得到充分研究。在本研究中，我们从人PIP4K2A蛋白的N端和C端区域鉴定出新型PIP4K2A模拟肽。进行了多肽敏感性试验，以评估它们对不同PTEN状态癌细胞活力的影响。体外分析表明，与PTEN野生型胶质瘤细胞（GL261）相比，peptide-1和peptide-2在PTEN缺陷型胶质瘤细胞（GL26）中表现出显著更高的敏感性。与这些发现一致，两种多肽在患者来源的肿瘤球模型中均显示出增强的抗肿瘤疗效。重要的是，在正常肝类器官和人角质形成细胞HaCaT细胞中未观察到显著毒性，表明其具有良好的治疗选择性。值得注意的是，peptide-1在PTEN缺陷型癌症的皮下患者来源异种移植模型中显著抑制了体内肿瘤生长。综上所述，这些结果确定peptide-1是一种有前景的、对PTEN缺陷型肿瘤具有选择性的基于多肽的治疗候选物，具有显著的临床转化潜力。
查看英文原文 English abstract
Tumor suppressor genes are essential for maintaining normal cellular development by restraining uncontrolled cell proliferation, and their inactivation is a hallmark of cancer progression. Peptide-based therapeutics have emerged as a promising treatment modality due to their high target specificity, biological activity, and favorable safety profiles. Among tumor suppressors, abnormalities in phosphatase and tensin homolog (PTEN) frequently arise from gene deletion, aberrant DNA methylation, or loss of functional protein expression. PTEN deficiency is observed in approximately 20-30% of human cancers and is closely associated with aggressive tumor behavior. Our previous studies identified that phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2A) has been identified as a negative regulator of tumor progression in PTEN-deficient cancers. However, peptide-based therapeutic strategies targeting the PIP4K2A pathway have not fully investigated. In this study, we identified novel PIP4K2A-mimetic peptides derived from the N- and C-terminal regions of the human PIP4K2A protein. Peptide sensitivity assays were conducted to assess their effects on cancer cell viability according to PTEN status. In vitro analyses demonstrated that peptide-1 and peptide-2 exhibited significantly greater sensitivity in PTEN-deficient glioma cells (GL26) compared with PTEN wild-type glioma cells (GL261). Consistent with these findings, both peptides showed enhanced antitumor efficacy in patient-derived tumorospheroid models. Importantly, no significant toxicity was observed in normal liver organoids and human keratinocyte HaCaT cells, indicating favorable therapeutic selectivity. Notably, peptide-1 markedly suppressed tumor growth in vivo in a subcutaneous patient-derived xenograft model of PTEN-deficient cancer. Collectively, these results identify peptide-1 as a promising peptide-based therapeutic candidate with selectivity for PTEN-deficient tumors and significant potential for clinical translation.
利益披露 Disclosure
J. Kim, None..
Y. Kwon, None..
Y. Shin, None..
J. Lee, None.