Oxidative stress induces senescence in breast cancer stem cells

Abstract

Cancer stem cells (CSCs) have been shown to be resistant to current anticancer therapies and the induction of oxidative stress is an important mechanism of action for many anticancer agents. However, it is still largely unknown how CSCs respond to hydrogen peroxide (H 2 O 2)-induced oxidative stress. Here, we show that the levels of reactive oxygen species (ROS) are markedly lower in breast CSCs (BCSCs) than that in non-cancer stem cells (NCSCs). A transient exposure of breast cancer cells to sublethal doses of H 2 O 2 resulted in a dose-dependent increase of the epithelium-specific antigen (ESA) + /CD44 + /CD24 − subpopulations, a known phenotype for BCSCs. Although BCSCs survived sublethal doses of H 2 O 2 treatment, they lost the ability to form tumor spheres and failed to generate colonies as demonstrated by mammosphere-formation and clonogenic assays, respectively. Mechanistic studies revealed that H 2 O 2 treatment led to a marked increase of senescence-associated β-galactosidase activity but only minimal apoptotic cell death in BCSCs. Furthermore, H 2 O 2 triggers p53 activation and promotes p21 expression, indicating a role for the p53/p21 signaling pathway in oxidative stress-induced senescence in BCSCs. Taken together, these results demonstrate that the maintenance of a lower level of ROS is critical for CSCs to avoid oxidative stress and H 2 O 2-induced BCSC loss of function is likely attributable to oxidative stress-triggered senescence induction, suggesting that ROS-generating drugs may have the therapeutic potential to eradicate drug-resistant CSCs via induction of premature senescence.

Targeting ferroptosis in breast cancer

“…In 2005, Ostrakhovitch et al demonstrated that activation of p53 played a crucial role in copper and zinc-induced generation of ROS in epithelial breast cancer cells via its target genes such as p53-induced gene 3 product (PIG3) and BAX [309]. Oxidative stress could also upregulate p53 to induce senescence in breast cancer cells [310]. P53 was found to be essential in PARP-mediated necrotic cell death induced by ROS in breast cancer cells [311].…”

Involvement of glutathione peroxidases in the occurrence and development of breast cancers

“…The development of drug resistance is a challenge for the use of adjuvant therapies in breast cancer patients [69], and studies suggest that ROS may play an important role in the production of drug-resistant cells [70]. Zhong et al demonstrated that oxidative stress and H 2 O 2 treatment led to a marked increase in senescence-associated β-galactosidase activity but only to minimal apoptotic cell death in CSCs, suggesting that ROS triggered the induction of senescence and exhibited therapeutic potential in the eradication of drug-resistant CSCs [8]. However, the increase in ROSs induced by drugs seems to play a different role compared to the role of ROS originally generated in malignant tumors.…”

“…Recent studies have shown that reactive oxygen species (ROS) are involved in the molecular mechanisms of breast cancer occurrence and development [7][8][9]; ROS can be regulated by glutathione peroxidases (GPxs), which are the key enzymes that maintain ROS homeostasis in vivo through the reduction of ROS [10]. Therefore, based on summaries of the research regarding the relationship between breast cancer and GPxs, this article focused on the molecular mechanism and function of different GPxs and their diverse roles in the occurrence and development of breast cancer, further clarifying the pathogenesis of breast cancer and providing a potential…”

Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness

“…Cancer stem cells seem to possess a lower ROS level than nontumoral stem cells, due to different mechanisms useful to reduce oxidative stress and maintain stem cell properties (404,(407)(408)(409). However, there are controversial aspects in the metabolism regulation of CSCs.…”

“…On the other hand, as it has been mentioned above, ROS is related to several cancer-promoting effects, thus it might be advantageous to reduce ROS levels or increase antioxidant molecules, in order to restore de redox balance in the cell. For these reasons, the efficacy of these anticancer strategies depends on the ROS level in the tumor type and the capacity of the tumor to modulate its metabolism routes (404,409,(412)(413)(414)(415)(416)(417)(418)(419).…”