Improved Autophagic Flux in Escapers from Doxorubicin-Induced Senescence/Polyploidy of Breast Cancer Cells

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.

Fucoxanthin Holds Potential to Become a Drug Adjuvant in Breast Cancer Treatment: Evidence from 2D and 3D Cell Cultures

“…Indeed, the presence of lipid droplets is thought to be part of stress response to treatments, regulation of proliferation, migration and survival of cancer cells [ 86 ]. The additional presence of a great number of autophagic vacuoles in the cytoplasm indicates that Dox induced autophagy in the MDA-MB-231 cell line, which agrees with a previous report [ 87 ].…”

Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP)

“…Even though most TIS/TIP cells remain senescent for several weeks or ultimately die, several studies indicated that this process is reversible and that polyploid cancer cells could depolyploidize (also termed “neosis” [ 129 , 131 ]). The reversibility of TIS/TIP-mediated senescence leads to regained proliferative capacity of mononucleated progenies [ 123 , 126 , 128 , 129 , 132 ] similar to previously described rejuvenation by retrodifferentiation [ 133 , 134 , 135 ].…”

“…Several studies suggested that cancer cells could escape from chemotherapeutic- or radiation-induced DNA damage by developing therapy-induced senescence (TIS). This could be further associated with therapy-induced polyploidization (TIP) resulting in the formation of multinucleated polyploid giant cells carrying ten or more subnuclei and micronuclei [ 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. Kaur and colleagues observed the origin of senescent multinucleated and giant cells after radiation and assumed that such polyploid cells were formed through radiation-induced homotypic cell fusions [ 130 ].…”

dl922-947 Adenovirus and G-Quadruplex Binder Combination Against Breast Cancer and Modulation of Monocyte Activity

“…5A). As reference compound, we used doxorubicin previously described to induce senescence in breast cancer cells (24). The observed effects were similar to those elicited by doxorubicin.…”