ArticleCell death and differentiation2021
BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer.
Article in Cell death and differentiation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 50 citations in OpenAlex.
- NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cytoplasmic p21 promotes stemness of colon cancer cells via activation of the NFκB pathway.Molecular oncology · 2026Article
- Ferroptosis as a Novel Therapeutic Strategy to Overcome Multidrug Resistance in Colorectal Cancer.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma.BMC medicine · 2026Article
- Elimination of docetaxel-induced senescence attenuates malignant progression in RB1-deficient CRPC.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Article
- GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells.Oncogenesis · 2025Article
- Spliceosome protein EFTUD2: A potential pathogenetic factor in tumorigenesis and some developmental defects (Review).Molecular medicine reports · 2025Review
- Selective BCL-2 inhibitor triggers STING-dependent antitumor immunity via inducing mtDNA release.Journal for immunotherapy of cancer · 2025Article
- UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer.Cell death and differentiation · 2025Article
- Model systems to study tumor-microbiome interactions in early-onset colorectal cancer.EMBO molecular medicine · 2025Review
- Senolytic agent ABT-263 mitigates low- and high-LET radiation-induced gastrointestinal cancer development inAging · 2025Article
- The role of mitochondria-associated ER membranes in disease pathology: protein complex and therapeutic targets.Frontiers in cell and developmental biology · 2025Review
- Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets.MedComm · 2024Review
- Exploring the Therapeutic Potential of 5-Fluorouracil-Loaded Calcium Carbonate Nanoparticles Combined with Natural Compound Thymoquinone for Colon Cancer Treatment.Pharmaceutics · 2024Article
- Review
- Tumor-targeted liposomes with platycodin D2 promote apoptosis in colorectal cancer.Materials today. Bio · 2023Review
- ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia.Nature communications · 2023Article
- High CD142 Level Marks Tumor-Promoting Fibroblasts with Targeting Potential in Colorectal Cancer.International journal of molecular sciences · 2023Article
- Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer.Animal models and experimental medicine · 2023Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 4 countries.
Funding
Abstract
Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upon APC-mutation driven transformation. Here we show that BCL-XL inhibition effectively impairs adenoma outgrowth in vivo and enhances the efficacy of chemotherapy. In line with this dependency, expression of BCL-XL, but not BCL-2 or MCL1, directly correlated to the outcome of chemotherapy-treated CRC patients. Our results provide insights to enable the rational use of BH3 mimetics in CRC management, particularly underlining the therapeutic potential of BCL-XL targeting mimetics in both early and late-stage disease.
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