Synergistic rescue of temperature-sensitive p53 mutants by hypothermia and arsenic trioxide.

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-11-01 Epub Date: 2024-08-08 DOI:10.1002/mc.23804
Junhao Lu, Lihong Chen, Zainab Fatima, Jeffrey Huang, Jiandong Chen
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Abstract

The p53 tumor suppressor is inactivated by mutations in about 50% of tumors. Rescuing the transcriptional function of mutant p53 has potential therapeutic benefits. Approximately 15% of p53 mutants are temperature sensitive (TS) and regain maximal activity at 32°C. Proof of concept study showed that induction of 32°C hypothermia in mice restored TS mutant p53 activity and inhibited tumor growth. However, 32°C is the lower limit of therapeutic hypothermia procedures for humans. Higher temperatures are preferable but result in suboptimal TS p53 activation. Recently, arsenic trioxide (ATO) was shown to rescue the conformation of p53 structural mutants by stabilizing the DNA binding domain. We examined the responses of 17 frequently observed p53 TS mutants to functional rescue by temperature shift and ATO. The results showed that ATO only rescued mild p53 TS mutants with high basal activity at 37°C. Mild TS mutants showed a common feature of regaining significant activity at the semi-permissive temperature of 35°C and could be further stimulated by ATO at 35°C. TS p53 rescue by ATO was antagonized by the cellular redox mechanism and was rapidly reversible. Inhibition of glutathione (GSH) biosynthesis enhanced ATO rescue efficiency and sustained p53 activity after ATO washout. The results suggest that mild TS p53 mutants are uniquely responsive to functional rescue by ATO due to small thermostability deficits and inherent potential to regain active conformation. Combining mild hypothermia and ATO may provide an effective and safe procedure for targeting tumors with p53 TS mutations.

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低体温和三氧化二砷对温度敏感的 p53 突变体的协同拯救。
在约 50% 的肿瘤中,p53 肿瘤抑制因子因突变而失活。恢复突变 p53 的转录功能具有潜在的治疗效果。大约 15%的 p53 突变体对温度敏感(TS),并在 32°C 时恢复最大活性。概念验证研究表明,对小鼠进行 32°C 低温诱导可恢复 TS 突变体 p53 的活性并抑制肿瘤生长。然而,32°C 是人类治疗性低温程序的下限。温度越高越好,但会导致 TS p53 激活效果不理想。最近,三氧化二砷(ATO)被证明能通过稳定 DNA 结合域来挽救 p53 结构突变体的构象。我们研究了 17 个经常观察到的 p53 TS 突变体对温度变化和 ATO 的功能拯救反应。结果表明,ATO只能拯救在37°C时具有高基础活性的轻度p53 TS突变体。轻度 TS 突变体的共同特点是在 35°C 的半耐受温度下恢复显著的活性,并能在 35°C 的温度下受到 ATO 的进一步刺激。细胞氧化还原机制拮抗了 ATO 对 TS p53 的拯救作用,而且这种作用是快速可逆的。抑制谷胱甘肽(GSH)的生物合成可提高 ATO 的解救效率,并在 ATO 清除后维持 p53 的活性。研究结果表明,轻度 TS p53 突变体对 ATO 的功能性拯救具有独特的响应性,这是因为它们具有较小的热稳定性缺陷和恢复活性构象的内在潜力。结合轻度低温和 ATO 可为针对 p53 TS 突变的肿瘤提供一种有效而安全的方法。
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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