Resistance to drugs and cell death in cancer stem cells (CSCs)

Abstract

Human cancers emerge from cancer stem cells (CSCs), which are resistant to cancer chemotherapeutic agents, radiation, and cell death. Moreover, autophagy provides the cytoprotective effect which contributes to drug resistance in these cells. Furthermore, much evidence shows that CSCs cause tumor initiation, progression, metastasis, and cancer recurrence. Various signaling pathways including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), maternal embryonic leucine zipper kinase (MELK), NOTCH1, and Wnt/β-catenin as well as the CSC markers maintain CSC properties. Several mechanisms including overexpression of ABC multidrug resistance transporters, a deficiency in mitochondrial-mediated apoptosis, upregulation of c-FLIP, overexpression of anti-apoptotic Bcl-2 family members and inhibitors of apoptosis proteins (IAPs), and PI3K/AKT signaling contribute to enhancing resistance to chemotherapeutic drugs and cell death induction in CSCs in various cancers. Studying such pathways may help provide detailed understanding of CSC mechanisms of resistance to chemotherapeutic agents and apoptosis and may lead to the development of effective therapeutics to eradicate CSCs.

Keywords: Bcl-2 family; anti-apoptotic proteins; apoptosis; c-FLIP; cancer stem cells (CSCs); death receptor pathways; drug resistance.

Figure 1.

Cancer stem cells (CSCs) role in tumor development and progression. CSCs are generated from the normal stem cells (NSCs) through tumorigenic transformation of several potential pathways including Hh: hedgehog, epithelial-to-mesenchymal transition (EMT), and the reverse process mesenchymal-to-epithelial transition (MET). CSCs and drug-induced CSCs (Di-CSCs) are enriched following conventional chemotherapy treatment

Figure 2.

Heterogeneity of CSCs in tumors. Development of drug resistant, metastatic tumors, and a potential strategy for eradicating tumors using CSC-specific drugs

Figure 3.

Schematic presentation of CSC-mediated therapy resistance to cancer. Activation of cell survival pathways, quiescence, increased drug efflux, impairment of the apoptotic pathway, increased DNA damage repair, increased detoxifying activity, and increased scavenging of free radicals are possible contributors to the therapy resistance of CSCs

Figure 4.

Apoptosis signaling pathways. Overview of the intrinsic (mitochondrial), extrinsic or death receptor (DR), and ER-stress (ERS)-mediated apoptosis pathways in response to the molecular action of anticancer agents as well as the TRADD/NF-κB survival pathway, the growth factor (GF) receptors, and PI3K/Akt pro-survival signaling axis in CSCs