Resistance to Cell Death and Its Modulation in Cancer Stem Cells

Abstract

Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs. Several 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—and expression of the CSC markers CD133, CD24, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain CSC properties. Studying such pathways may help to understand CSC biology and lead to the development of potential therapeutic interventions to render CSCs more sensitive to cell death triggered by chemotherapy and radiation therapy. Moreover, recent demonstrations of dedifferentiation of differentiated cancer cells into CSC-like cells have created significant complexity in the CSCs hypothesis. Therefore, any successful therapeutic agent or combination of drugs for cancer therapy must eliminate not only CSCs but differentiated cancer cells and the entire bulk of tumor cells. This review article expands on the CSC hypothesis and paradigm with respect to major signaling pathways and effectors that regulate CSC apoptosis resistance. Moreover, selective CSC apoptotic modulators and their therapeutic potential for making tumors more responsive to therapy are discussed. The use of novel therapies, including small-molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of CSCs, immunotherapy, and noncoding microRNAs may provide better means of treating CSCs.

miR‐26b‐5p helps in EpCAM+cancer stem cells maintenance via HSC71/HSPA8 and augments malignant features in HCC

“…Resistance to apoptosis is a hallmark of CSCs . We therefore evaluated whether miR‐26b‐5p plays any role in regulating apoptosis of HCC cells.…”

Long non‐coding RNA FEZF1‐AS1 promotes breast cancer stemness and tumorigenesis via targeting miR‐30a/Nanog axis

“…Besides, FEZF1‐AS1 knockdown decreased the expression of stem factors (Nanog, Oct4, SOX2). It is well‐known that cancer‐stem like cells endow the growth or proliferation potential in residual surgical resection or post‐chemoradiotherapy (Liu, Choi, et al, ; Lo, Wolfson, & Zhou, ; Mansoori, Madjd, Janani, & Rasti, ; Safa, ). Therefore, our results revealed that FEZF1‐AS1 could promote the BCSC properties through positively accelerating the stemness.…”

In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non–small‐cell lung cancer

“…CD133 and Oct‐4A, the CSC markers, have been suggested as protectors for cancer cells from apoptosis induced by chemotherapeutic agents . Significantly increased apoptosis‐related proteins—cleaved caspase‐3 and cleaved PARP—were observed in cells treated with gemcitabine plus thiostrepton (Figure C).…”

“…CD133 and Oct-4A, the CSC markers, have been suggested as protectors for cancer cells from apoptosis induced by chemotherapeutic agents. 25,26,36 Significantly increased apoptosis-related proteins-cleaved caspase-3 and cleaved PARP-were observed in cells treated with gemcitabine plus thiostrepton ( Figure 4C). Apoptosis induced by gemcitabine plus thiostrepton was more significant compared with that induced by gemcitabine or thiostrepton alone ( Figure 4C).…”