Interconnection of CD133 Stem Cell Marker with Autophagy and Apoptosis in Colorectal Cancer

Abstract

CD133 protein expression is observable in differentiated cells, stem cells, and progenitor cells within normal tissues, as well as in tumor tissues, including colorectal cancer cells. The CD133 protein is the predominant cell surface marker utilized to detect cancer cells exhibiting stem cell-like characteristics. CD133 alters common abnormal processes in colorectal cancer, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin pathways. Autophagy is a cellular self-digestion mechanism that preserves the intracellular milieu and plays a dual regulatory role in cancer. In cancer cells, apoptosis is a critical cell death mechanism that can impede cancer progression. CD133 can modulate autophagy and apoptosis in colorectal cancer cells via several signaling pathways; hence, it is involved in the regulation of these intricate processes. This can be an explanation for why CD133 expression is associated with enhanced cellular self-renewal, migration, invasion, and survival under stress conditions in colorectal cancer. The purpose of this review article is to explain the complex relationship between the CD133 protein, apoptosis, and autophagy. We also want to highlight the possible ways that CD133-mediated autophagy may affect the apoptosis of colorectal cancer cells. Targeting the aforementioned mechanisms may have a significant therapeutic role in eliminating CD133-positive stem cell-phenotype colorectal cancer cells, which can be responsible for tumor recurrence.

Keywords: CD133; apoptosis; autophagy; colorectal cancer; stem cell.

Figure 1

The structure of CD133. Five membrane-spanning domains make up CD133, with the N-terminal domain (NH2) exposed to the extracellular milieu, four alternating short cytoplasmic and large glycosylated (red symbols) extracellular loops, and a cytoplasmic C-terminal domain (COOH). A large number possess unique cytoplasmic C-terminal domains, which may suggest the presence of a variety of cytoplasmic protein-interacting partners. EC: extracellular domain; IC: intracellular domain. The figure was partially created with https://www.biorender.com (accessed on 20 September 2024).

Figure 2

Several CD133 mechanisms have been suggested for CRC control. Notch activation effectively inhibits apoptosis by upregulating anti-apoptotic genes such as Hes1 and Hes5, as well as engaging with the PI3K/AKT pathway. The initiation of this signaling cascade allows CD133+ cells to evade apoptosis and preserve their stem-like properties. Activated CD133 physically interacts with WNT, resulting in elevated β-catenin levels. The β-catenin subsequently translocates to the nucleus, culminating in enhanced transcription of WNT target genes, which promotes stemness and proliferation of cancer cells. Activated CD133 phosphorylates the p85 subunit of PI3Ks. This cascade of molecular activations subsequently leads to the activation of AKT, which enhances stemness and proliferation. In addition, AKT turns on the NF-κB pathway, which increases the production of MDR-1 and makes cells chemoresistant. HES: hairy and enhancer of split; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; NF-kB: nuclear factor kappa B. The figure was partially created with https://www.biorender.com (accessed on 20 September 2024).

Figure 3

Inhibiting CD133 function in colorectal cancer stem cells (e.g., through CD133 silencing RNAs) may enhance cancer stem cell chemosensitivity by decreasing ABCB1 or MDR1 expression. Additionally, it attenuates the self-renewal potential of cancer stem cells, as well as cell proliferation, invasion, and migration, by modifying the PI3K/AKT/mTOR pathway and diminishing HER2 expression and EGFR activity. siRNA: silencing ribonucleic acid; ABCB1: ATP binding cassette subfamily B member 1; MDR1: multidrug resistance 1; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; mTOR: mechanistic target of rapamycin; HER2: human epidermal growth factor receptor 2; EGFR: epidermal growth factor receptor. The figure was partially created with https://www.biorender.com (accessed on 20 September 2024).

Figure 4

Correlation of autophagy and apoptosis with CD133 in colorectal cancer. Suppressing autophagy through the attenuation of epithelial–mesenchymal transition diminishes apoptosis resistance, ultimately leading to the demise of cancer cells. Inhibition of autophagy reduces the expression of anti-apoptotic proteins in CD133+ cancer cells, resulting in death due to mitochondrial membrane instability. Chemotherapeutic medicines, autophagy gene suppression, or antimalarial medications can reduce or block the autophagy process. Chemotherapy or irradiation may simultaneously decrease apoptosis by promoting stress-induced autophagy, which facilitates the repair of damaged cellular components. EMT: epithelial–mesenchymal transition; 5-FU: 5-fluorouracil; ATG5: autophagy protein 5; Bcl-xL: B-cell lymphoma-extra-large; Mcl-1: myeloid cell leukemia-1; red arrows: decrease; green arrows: increase. The figure was partially created with https://www.biorender.com (accessed on 9 October 2024).

Figure 5

Targeted therapeutic options for CD133 and related molecules represent a new approach to the treatment of colorectal cancer. ICI: immune checkpoint inhibitor; PD-1: programmed cell death protein 1; CTLA-4: cytotoxic T-lymphocyte associated protein 4; CAR T: chimeric antigen receptor T cell; HIF-1α: hypoxia-inducible factor 1α; BH3: B-cell lymphoma 2 Homology 3; siRNA: small interfering RNA; CRISPR: clustered regularly interspaced short palindromic repeats; CSC: cancer stem cell. The figure was partially created with https://www.biorender.com (accessed on 9 October 2024).