ATM Pathway Is Essential for HPV-Positive Human Cervical Cancer-Derived Cell Lines Viability and Proliferation

Autor(es)

Abjaude, Walason ; Prati, Bruna ; Munford, Veridiana ; Montenegro, Aline ; Lino, Vanesca ; Herbster, Suellen ; Rabachini, Tatiana ; Termini, Lara ; Menck, Carlos Frederico Martins ; Boccardo, Enrique

• Tipo de documento: Artigo Científico
• Fonte: PATHOGENS; v. 11, n. 6, p. 19-pg., 2022-06-01.

Resumo

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. (AU)

• Processo FAPESP: 17/02997-3 - Papel da proteína RECK no processo de transformação celular mediado por HPV
• Beneficiário: Enrique Mario Boccardo Pierulivo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/27006-9 - Estudo do papel da proteína reck no processo de carcinogênese mediado pelo papilomavírus humano
• Beneficiário: Suellen da Silva Gomes Herbster
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/16512-8 - Estudo de Letalidade Sintética em células transformadas por papilomavírus humano (HPV)
• Beneficiário: Walason da Silva Abjaude
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 10/20002-0 - Estudo de Letalidade Sintética em células infectadas por papilomavírus humano (HPV)
• Beneficiário: Enrique Mario Boccardo Pierulivo
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 19/19435-3 - Papel de danos no DNA e função mitocondrial em envelhecimento vascular, imune e neurológico (DNA MoVINg)
• Beneficiário: Carlos Frederico Martins Menck
• Modalidade de apoio: Auxílio à Pesquisa - Temático