Abstract
Anticancer therapies that induce DNA damage tend to trigger senescence in cancer cells, a process known as therapy-induced senescence (TIS). Such cells may undergo atypical divisions, thus contributing to tumor re-growth. Accumulation of senescent cancer cells reduces survival of patients after chemotherapy. As senescence interplays with autophagy, a dynamic recycling process, we sought to study whether inhibition of autophagy interferes with divisions of TIS cells. We exposed human colon cancer HCT116 cells to repeated cycles of a chemotherapeutic agent – doxorubicin (doxo) and demonstrated induction of hallmarks of TIS (e.g. growth arrest, hypertrophy, poliploidization and secretory phenotype) and certain properties of cancer stem cells (increased NANOG expression, percentages of CD24+ cells and side population). Colonies of small and highly proliferative progeny appeared shortly after drug removal. Treatment with bafilomycin A1 (BAF A1), an autophagy inhibitor, postponed short term in vitro cell re-population. It was associated with reduction in the number of diploid and increase in the number of poliploid cells. In a long term, a pulse of BAF A1 resulted in reactivation of autophagy in a subpopulation of HCT116 cells and increased proliferation. Accordingly, the senescent HCT116 cells treated with BAF A1 when injected into NOD/SCID mice formed tumors, in contrast to the controls.Our results suggest that senescent cancer cells that appear during therapy, can be considered as dormant cells that contribute to cancer re-growth, when chemotherapeutic treatment is stopped. These data unveil new mechanisms of TIS-related cancer maintenance and re-population, triggered by a single pulse of BAF A1 treatment.
Highlights
Colon cancer is the third most common cause of cancer-related mortality in the US [1]
We treated HCT116 colon cancer cells with three www.impactjournals.com/oncotarget doxorubicin cycles to obtain more stable and homogenous population of senescent cells [48] and to mimic processes occurring in cancer patients subjected to repeated chemotherapy cycles over long time
We demonstrate that in response to the treatment, a majority of HCT116 cells showed features of senescence exemplified by flatten morphology and increased size, growth arrest, polyploidy, augmented SA-β-Gal and senescence-associated secretory phenotype (SASP)
Summary
Colon cancer is the third most common cause of cancer-related mortality in the US [1]. A growing body of evidence supports correlation between accumulation of TIS cancer cells and reduced survival of patients subjected to anticancer treatment [5, 8,9,10,11, 14]. This could be attributed to SASP-related remodeling of tumor environment [5, 15] and/or atypical senescent cell divisions [16,17,18]. Quiescent or slow cycling CSCs may survive therapeutic intervention, which results in tumor relapse [21]
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