Abjaude Walason, Prati Bruna, Munford Veridiana, Montenegro Aline, Lino Vanesca, Herbster Suellen, Rabachini Tatiana, Termini Lara, Menck Carlos Frederico Martins, Boccardo Enrique
Laboratory of Oncovirology, Department of Microbiology, Instituto de Ciências Biomédicas, Universidade de São Paulo, Sao Paulo 05508-900, Brazil.
Laboratory of DNA Repair, Department of Microbiology, Instituto de Ciências Biomédicas, Universidade de São Paulo, Sao Paulo 05508-000, Brazil.
Pathogens. 2022 Jun 1;11(6):637. doi: 10.3390/pathogens11060637.
Infection with some mucosal human papillomavirus (HPV) types is the etiological cause of cervical cancer and of a significant fraction of vaginal, vulvar, anal, penile, and head and neck carcinomas. DNA repair machinery is essential for both HPV replication and tumor cells survival suggesting that cellular DNA repair machinery may play a dual role in HPV biology and pathogenesis. Here, we silenced genes involved in DNA Repair pathways to identify genes that are essential for the survival of HPV-transformed cells. We identified that inhibition of the ATM/CHK2/BRCA1 axis selectively affects the proliferation of cervical cancer-derived cell lines, without altering normal primary human keratinocytes (PHK) growth. Silencing or chemical inhibition of ATM/CHK2 reduced the clonogenic and proliferative capacity of cervical cancer-derived cells. Using PHK transduced with HPV16 oncogenes we observed that the effect of ATM/CHK2 silencing depends on the expression of the oncogene E6 and on its ability to induce p53 degradation. Our results show that inhibition of components of the ATM/CHK2 signaling axis reduces p53-deficient cells proliferation potential, suggesting the existence of a synthetic lethal association between CHK2 and p53. Altogether, we present evidence that synthetic lethality using ATM/CHK2 inhibitors can be exploited to treat cervical cancer and other HPV-associated tumors.
某些黏膜型人乳头瘤病毒（HPV）感染是宫颈癌以及相当一部分阴道癌、外阴癌、肛门癌、阴茎癌和头颈癌的病因。DNA修复机制对于HPV复制和肿瘤细胞存活均至关重要，这表明细胞DNA修复机制可能在HPV生物学和发病机制中发挥双重作用。在此，我们使参与DNA修复途径的基因沉默，以鉴定对HPV转化细胞存活至关重要的基因。我们发现抑制ATM/CHK2/BRCA1轴会选择性地影响宫颈癌来源细胞系的增殖，而不会改变正常原代人角质形成细胞（PHK）的生长。对ATM/CHK2进行沉默或化学抑制会降低宫颈癌来源细胞的克隆形成能力和增殖能力。使用转导了HPV16癌基因的PHK，我们观察到ATM/CHK2沉默的效果取决于癌基因E6的表达及其诱导p53降解的能力。我们的结果表明，抑制ATM/CHK2信号轴的成分会降低p53缺陷细胞的增殖潜能，这表明CHK2和p53之间存在合成致死关联。总之，我们提供的证据表明，使用ATM/CHK2抑制剂的合成致死性可用于治疗宫颈癌和其他HPV相关肿瘤。
