Autophagy buffers Ras-induced genotoxic stress enabling malignant transformation in keratinocytes primed by human papillomavirus.

Autor: Cararo-Lopes E; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, SP, 05503-900, Brazil. edu.llopes@gmail.com.; Department of Biochemistry, Instituto de Química, Universidade de São Paulo, São Paulo, SP, 05508-000, Brazil. edu.llopes@gmail.com.; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. edu.llopes@gmail.com., Dias MH; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, SP, 05503-900, Brazil., da Silva MS; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, SP, 05503-900, Brazil.; Department of Chemical and Biological Sciences, Instituto de Biociência, Universidade do Estado de São Paulo, Botucatu, SP, 18618-689, Brazil., Zeidler JD; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, SP, 05503-900, Brazil.; Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA., Vessoni AT; Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA., Reis MS; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, SP, 05503-900, Brazil., Boccardo E; Department of Microbiology, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil., Armelin HA; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, SP, 05503-900, Brazil. haarmelin@iq.usp.br.; Department of Biochemistry, Instituto de Química, Universidade de São Paulo, São Paulo, SP, 05508-000, Brazil. haarmelin@iq.usp.br.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2021 Feb 18; Vol. 12 (2), pp. 194. Date of Electronic Publication: 2021 Feb 18.
DOI: 10.1038/s41419-021-03476-3
Abstrakt: Malignant transformation involves an orchestrated rearrangement of cell cycle regulation mechanisms that must balance autonomic mitogenic impulses and deleterious oncogenic stress. Human papillomavirus (HPV) infection is highly prevalent in populations around the globe, whereas the incidence of cervical cancer is 0.15%. Since HPV infection primes cervical keratinocytes to undergo malignant transformation, we can assume that the balance between transforming mitogenic signals and oncogenic stress is rarely attained. We showed that highly transforming mitogenic signals triggered by HRas G12V activity in E6E7-HPV-keratinocytes generate strong replication and oxidative stresses. These stresses are counteracted by autophagy induction that buffers the rapid increase of ROS that is the main cause of genotoxic stress promoted by the oncoprotein. As a result, autophagy creates a narrow window of opportunity for malignant keratinocytes to emerge. This work shows that autophagy is crucial to allow the transition of E6E7 keratinocytes from an immortalized to a malignant state caused by HRas G12V .
Databáze: MEDLINE
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