Abstract
Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.
Highlights
Accelerated or premature senescence is a common tumor cell response to conventional cancer therapy [1,2]
Recent studies have strongly suggested that the senescent growth arrest precipitated by anticancer therapy [therapy-induced senescence (TIS)] is not terminal, and that a subpopulation of the senescent tumor cells can resume division, a process termed proliferative recovery [5,6]
Our first series of studies examined the induction of senescence and autophagy in H460 non-small cell lung cancer cells exposed to etoposide
Summary
Accelerated or premature senescence is a common tumor cell response to conventional cancer therapy [1,2]. Senescent tumor cells are growth-arrested and exhibit flat and hypertrophic cellular morphology, increased activity of the lysosomal senescence-associated β-galactosidase (SA-β-gal), epigenetic changes, as well as a genetic expression profile reflective of the senescence-associated secretory phenotype (SASP) [3]. Due to the durable nature of the senescent growth arrest, the use of senescence-inducing agents is considered an adventitious approach for cancer therapy based on the promotion of a static barrier against further tumor growth [4]. Recent studies have strongly suggested that the senescent growth arrest precipitated by anticancer therapy [therapy-induced senescence (TIS)] is not terminal, and that a subpopulation of the senescent tumor cells can resume division, a process termed proliferative recovery [5,6]. The SASP has been shown to potentially promote tumor growth [10]
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