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Reversibility of chemotherapy-induced senescence is independent of autophagy and a potential model for tumor dormancy and cancer recurrence.

By Tareq Saleh, Emmanuel K Cudjoe, S. Lauren Kyte, Scott C Henderson, Lynne W Elmore, David A. Gewirtz

Posted 11 Jan 2017
bioRxiv DOI: 10.1101/099812

Autophagy and senescence are both well-established responses to chemotherapy and radiation that often occur in parallel, contributing to growth arrest in tumor cells. However, it has not been established whether this growth arrest is reversible. This question was addressed using non-small cell lung cancer models exposed to the cancer chemotherapeutic drug, etoposide. Senescent cells that were sorted, identified by β-galactosidase staining and alterations in morphology, isolated by flow cytometric cell sorting based on C12FDG staining, and real-time live microscopy were found to be capable of recovering proliferative capacity. Autophagy, monitored by vacuole formation, SQSTM1/p62 degradation, and LC3BII generation did not interfere with either the senescence arrest or proliferative recovery and was nonprotective in function (i.e. autophagy inhibition via both pharmacological and genetic strategies had negligible impact on the response to etoposide). These observations argue against the premise that (chemotherapy-induced) senescence is irreversible and indicate that therapy-induced senescence may ultimately be a transient process in that at least a subpopulation of tumor cells can and will remain metabolically active and recover proliferative capacity independently of autophagic turnover. We therefore propose that dormant tumor cells may be capable of prolonged survival in a state of autophagy/senescence and that disease recurrence may reflect escape from this senescence-arrested state.

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