Abstract
The induction of senescence/polyploidization and their role in cancer recurrence is still a poorly explored issue. We showed that MDA-MB-231 and MCF-7 breast cancer cells underwent reversible senescence/polyploidization upon pulse treatment with doxorubicin (dox). Subsequently, senescent/polyploid cells produced progeny (escapers) that possessed the same amount of DNA as parental cells. In a dox-induced senescence/polyploidization state, the accumulation of autophagy protein markers, such as LC3B II and p62/SQSTM1, was observed. However, the senescent cells were characterized by a very low rate of new autophagosome formation and degradation, estimated by autophagic index. In contrast to senescent cells, escapers had a substantially increased autophagic index and transcription factor EB activation, but a decreased level of an autophagy inhibitor, Rubicon, and autophagic vesicles with non-degraded cargo. These results strongly suggested that autophagy in escapers was improved, especially in MDA-MB-231 cells. The escapers of both cell lines were also susceptible to dox-induced senescence. However, MDA-MB-231 cells which escaped from senescence were characterized by a lower number of γH2AX foci and a different pattern of interleukin synthesis than senescent cells. Thus, our studies showed that breast cancer cells can undergo senescence uncoupled from autophagy status, but autophagic flux resumption may be indispensable in cancer cell escape from senescence/polyploidy.
Highlights
Despite the spectacular progress in cancer treatment made during recent years, some types of aggressive cancer are still able to spread and become resistant to anticancer treatment
MCF-7 cells with a 25 times higher autophagic index than MDA-MB-231 cells (Figure 5d) had similar vulnerability to dox (Figure S4a) and underwent dox-induced senescence, as we previously described in detail [38]
Our results show that autophagic flux in control MDA-MB-231 cells, and avbeorrytilvowe,aiuttiospshufafgicyieinntdfourcctieollnsuinrvsievnaleascnedndticveislilos.n.InDocox-nintrdausctetdostehniess,ctehneceapispaesasroacinacteedowf sitehntehsecence escapmeenrohsdaiunslcaaetcmioceonnmot fipnaauanutiotepodphhabgayygt-icrheefgluudxlea.ctTerhdeiaspsmaetahinywbaaeuysta,ossspuohccaihagtaeiscdmmwTaitOrhkRtehraesnidamnApdaMiarPmuKteo,npht ohowfagdeivecgerrfl,audwxaittrihoeonsuuftumvnipcstitibioolnen. 2.5
Summary
Despite the spectacular progress in cancer treatment made during recent years, some types of aggressive cancer are still able to spread and become resistant to anticancer treatment. Beside division arrest and secretory activity, known as the senescenceassociated secretory phenotype (SASP), are, to senescent normal cells, characterized by many other features, such as the increased activity of senescence-associated β-galactosidase (SA-β-gal), lipofuscin and lipid droplet accumulation, altered morphology (flattening and increased granularity), an increased level of cyclin-dependent kinase inhibitors, such as p16INK4A and p21WAF1/CIP1 [15], increased lysosomal mass [16], morphologically and functionally altered mitochondria [17] and DNA double-strand breaks (DSBs) The latter induces the so-called DNA damage response (DDR) signaling pathway [18]. We were interested in propensity to undergo senescence and autophagy activity in the escapers
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