Autophagy buffers Ras-induced genotoxic stress enabling malignant transformation in keratinocytes primed by human papillomavirus
Open Access
- 18 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (2), 1-16
- https://doi.org/10.1038/s41419-021-03476-3
Abstract
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).Keywords
Funding Information
- Ministry of Science, Technology and Innovation | Conselho Nacional de Desenvolvimento Científico e Tecnológico
This publication has 62 references indexed in Scilit:
- RAS oncogenes: weaving a tumorigenic webNature Reviews Cancer, 2011
- Autophagy in tumorigenesis and energy metabolism: friend by day, foe by nightCurrent Opinion in Genetics & Development, 2011
- Role of autophagy in suppression of inflammation and cancerCurrent Opinion in Cell Biology, 2010
- Autophagy Suppresses Tumorigenesis through Elimination of p62Cell, 2009
- Principles of Cancer Therapy: Oncogene and Non-oncogene AddictionCell, 2009
- Replication fork movement sets chromatin loop size and origin choice in mammalian cellsNature, 2008
- Autophagy fights disease through cellular self-digestionNature, 2008
- Autophagy in the Pathogenesis of DiseaseCell, 2008
- Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replicationNature, 2006
- Activation of the DNA damage checkpoint and genomic instability in human precancerous lesionsNature, 2005