Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces

Abstract

Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

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

Figure 1

Heterogeneity of CSCs in tumors. Development of drug-resistance phenotype, metastatic tumor formation, and a potential strategy for eradicating tumors using CSC-specific drugs. CSC: Cancer stem cell.

Figure 2

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

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. TRADD: Tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein.

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 prosurvival signaling axis in CSCs. FADD: Fas-associated death domain; c-FLIP: cellular FLICE-like inhibitory protein; TRAF: tumor necrosis factor receptor associated factor; NF-κB: nuclear factor kappa B; IkB: inhibitor kappa B; IKK: inhibitor kappa B kinase; XIAP: X-linked inhibitor of apoptosis; Apaf-1: apoptotic Protease Activating Factor-1; Cyt. C: cytochrome c; PI3kinase: phosphoinositide 3-kinase; AKT: protein kinase B (PKB); PUMA: p53upregulated modulator of apoptosis; Bcl-2: B cell Lymphoma 2; Bax: Bcl-2-associated X protein; BID: BH3 interacting domain death agonist; Mcl-1: myeloid cell leukemia sequence 1; Bak: BCL-2-anatagonist/killer1; CHOP: C/EBP homologous protein; Noxa: encodes a Bcl-2 homology 3 (BH3) member of the Bcl-2 family of proteins; ATF: activating transcription factor; ER: endoplasmic reticulum; PERK: endoplasmic reticulum stress kinase; IRE1: inositol-requiring enzyme 1; RYR: ryanodine receptors Ca2+ release channels; IP3R: inositol 1,4,5-trisphosphate (IP3) regulated channels; BIP: binding immunoglobulin protein.