Redox-Regulation in Cancer Stem Cells

Abstract

Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.

Keywords: CD13; Nrf2-sinaling; ROS; Sonic Hedgehog signaling; Wnt-signaling; antioxidant signaling pathways; cancer stem cell; drug resistance.

Figure 1

Pathways contributing to the maintenance of the cancer stem cell (CSC) phenotype. Keeping intracellular ROS levels low is required for a stem cell to maintain quiescence and self-renewal properties. This is achieved to a large extent by expression of Nrf2-induced target genes. Thereby, antioxidative defense molecules and detoxifying enzymes including thioredoxin, peroxiredoxin, glutathione-S-transferases, heme oxygenase I are provided to keep the levels of reactive oxygen species derived from, e.g., NADH oxidases (NOX), the respiratory chain, infiltrating/surrounding immune cells, or chemotherapeutic drugs low. Nrf2 and pathways initiated by the CSC surface receptors and markers to minimize ROS production in response to chemotherapeutics like Sonic Hedgehog, Wnt family members, CD13, CD44 or CD133 add to the strong induction of drug efflux transporters. In addition, pathways that contribute to the CSC phenotype act via preventing apoptosis, promoting angiogenesis and expression of stem cell transcription factors such as NANOG homeobox (NANOG HOMEOBOX) and SRY-box transcription factor 2 (SOX2). Note that the canonical β-catenin-dependent Wnt pathway, and GSK-3β in particular, is a downstream mediator shared by many of the CSC markers and CSC pathways.

Figure 2

Nrf2 signaling pathway activation by ROS and induction of target genes. Under physiological conditions, NRF2 bound to KEAP1 is ubiquitylated and degraded in the proteasome. In response to ROS and various other stress factors, KEAP1 is released from NRF2, leading to its stabilization and translocation into the nucleus. Target gene expression is induced upon binding of NRF2 to AREs (antioxidant response element) in the promoters of target genes. Target genes comprise genes coding for the cell’s antioxidative equipment, efflux pumps enabling drug resistance, stemness-regulating transcription factors, as well as SHH (modified from [71,72]).