《自然通讯》：一种蛋白质可以作为肺癌治疗靶点

资讯作者：Virginia Commonwealth University

编辑翻译：菁菁

译文校对：奇奇

文献在2021年4月最新的美国医学学术期刊《自然通讯》首次刊发。文献中，科学家发现一种蛋白质，该蛋白质具有特定的基因突变，且能够刺激肺癌发展。他们还发现，该蛋白质可以作为治疗该疾病的靶标。

VCU梅西癌症中心（VCU Massey Cancer Center）的科学家发现一种蛋白质，该蛋白质具有特定的基因突变，且能够刺激肺癌发展。他们还发现，该蛋白质可以作为治疗该疾病的靶标。

研究人员在一半以上的癌症中都发现了p53基因突变。但是即使在发现该基因几十年后，仍然很难用药物有效地靶向该基因。先前的研究表明，在自然状态下，p53可以充当肿瘤抑制因子并诱导癌细胞死亡。但由Sumitra Deb博士主导的一项新研究表明，功能性基因突变的附加作用之一是将p53转变为致癌基因，导致细胞不受控制地复制，并促使癌症发展。 

这一发现于近日发表在《自然通讯》上。研究人员确定，突变的p53基因受特定蛋白质PLK3的影响，可以通过反激活过程，复制遗传密码、促进肿瘤细胞的增殖。 

使用由功能获得性突变p53驱动的肺癌临床前模型，Deb和他的研究小组发现PLK3激活了一种名为丝氨酸20（S20）的氨基酸，这种氨基酸在癌细胞复制中起着重要作用。 

通过抑制功能获得性突变 p53细胞中的PLK3，他们观察到S20功能下调、出现反激活过程，肿瘤细胞形成总体上减缓。 

Deb是梅西癌症生物学研究项目的成员，也是VCU医学院生物化学与分子生物学系的教授。他说：“我们的研究表明，功能获得性突变p53利用PLK3来触发其转活化能力，并发挥致癌作用。这一发现表明，研究人员有望使用PLK3抑制剂靶向p53驱动的癌细胞。” 

Deb的团队将继续挖掘PLK3抑制剂的潜力，验证其在肺癌以及其他具有相同基因突变的潜在疾病类型中是否具有相应疗效。

英文原文

Scientists Identify Protein That Could Serve as a Therapeutic tArget in Lung Cancer

Scientists at VCU Massey Cancer Center have identified a protein that operates in tandem with a specific genetic mutation to spur lung cancer growth and could serve as a therapeutic target to treat the disease.

Mutations in the p53 gene are found in more than half of all cancers, but it remains difficult to effectively target the gene with drugs even decades after its discovery. Though previous research has shown that p53 acts as a tumor suppressor and initiates cancer cell death in its natural state, a new study led by Sumitra Deb, Ph.D., suggests that gain-of-function (GOF) mutations—a type of mutation where the changed gene has an added function—turn p53 into an oncogene, causing cells to replicate uncontrollably and contribute to cancer development.

Recently published in Nature Communications, the researchers determined that mutant p53 genes are empowered by a specific protein, PLK3, to copy their genetic code and promote tumor cell proliferation through a process called transactivation.

Using preclinical models of lung cancer driven by p53 GOF mutations, Deb and his research team discovered that PLK3 activates an amino acid called serine 20 (S20), a cellular building block they found to play an important role in cancer cell replication.

By inhibiting PLK3 in GOF p53 mutant cells, they observed a decrease in the function of S20 along with overall reductions in transactivation and tumor cell formation.

"Our research indicates that GOF p53 exploits PLK3 to trigger its transactivation capability and exert oncogenic functions, raising the possibility of targeting p53-driven cancer cells using PLK3 inhibitors," said Deb, a member of the Cancer Biology research program at Massey and professor in the Department of Biochemistry and Molecular Biology at the VCU School of Medicine.

Deb's team will continue to explore the potential for PLK3 inhibitors to be effective drugs in the treatment of lung cancer and potentially other forms of disease with the same genetic mutation.

参考文献

More information: Catherine A. Vaughan et al, The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3, Nature Communications (2021). 

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