ArticleThe Journal of biological chemistry2015
The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 57 citations in OpenAlex.
- Cellular signaling meets bacterial infection: the integrative role of STAT3.Frontiers in cellular and infection microbiology · 2026Review
- Multifaceted roles of microbiota-derived deoxycholic acid in gastrointestinal cancers: from barrier disruption to therapeutic implications.Human cell · 2025Review
- Screening a living biobank identifies cabazitaxel as a strategy to combat acquired taxol resistance in high-grade serous ovarian cancer.Cell reports. Medicine · 2025Article
- Combination of KRAS ASO and RIG-I agonist in extracellular vesicles transforms the tumor microenvironment towards effective treatment of KRAS-dependent cancers.Theranostics · 2025Article
- A comprehensive benchmarking of machine learning algorithms and dimensionality reduction methods for drug sensitivity prediction.Briefings in bioinformatics · 2024Article
- Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer.The Journal of clinical investigation · 2023Article
- The role of curcumin on apoptosis and NLRP3 inflammasome-dependent pyroptosis on colorectal cancer in vitro.Turkish journal of medical sciences · 2023Article
- STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges.Seminars in cancer biology · 2022Review
- Crucial Role of OncogenicCells · 2022Review
- Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics.Cancer discovery · 2022Review
- Review
- Expression of Parkin, APC, APE1, and Bcl-xL in Colorectal Polyps.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2021Article
- Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage.Cell communication and signaling : CCS · 2021Review
- Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia.Nature cancer · 2020Article
- Curcumin-Mediated Apoptotic Cell Death in Papillary Thyroid Cancer and Cancer Stem-Like Cells through Targeting of the JAK/STAT3 Signaling Pathway.International journal of molecular sciences · 2020Article
- P-STAT3 Inhibition Activates Endoplasmic Reticulum Stress-Induced Splenocyte Apoptosis in Chronic Stress.Frontiers in physiology · 2020Article
- Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity.Cancers · 2019Review
- BRAFOncogene · 2019Article
- A Cell's Fate: An Overview of the Molecular Biology and Genetics of Apoptosis.International journal of molecular sciences · 2019Review
- Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy.Molecules (Basel, Switzerland) · 2019Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
In colorectal cancers with oncogenic GTPase Kras (KRAS) mutations, inhibition of downstream MEK/ERK signaling has shown limited efficacy, in part because of failure to induce a robust apoptotic response. We studied the mechanism of apoptosis resistance in mutant KRAS cells and sought to enhance the efficacy of a KRAS-specific MEK/ERK inhibitor, GDC-0623. GDC-0623 was shown to potently up-regulate BIM expression to a greater extent versus other MEK inhibitors in isogenic KRAS HCT116 and mutant KRAS SW620 colon cancer cells. ERK silencing enhanced BIM up-regulation by GDC-0623 that was due to its loss of phosphorylation at Ser(69), confirmed by a BIM-EL phosphorylation-defective mutant (S69G) that increased protein stability and blocked BIM induction. Despite BIM and BIK induction, the isogenic KRAS mutant versus wild-type cells remained resistant to GDC-0623-induced apoptosis, in part because of up-regulation of BCL-XL. KRAS knockdown by a doxycycline-inducible shRNA attenuated BCL-XL expression. BCL-XL knockdown sensitized KRAS mutant cells to GDC-0623-mediated apoptosis, as did the BH3 mimetic ABT-263. GDC-0623 plus ABT-263 induced a synergistic apoptosis by a mechanism that includes release of BIM from its sequestration by BCL-XL. Furthermore, mutant KRAS activated p-STAT3 (Tyr(705)) in the absence of IL-6 secretion, and STAT3 knockdown reduced BCL-XL mRNA and protein expression. These data suggest that BCL-XL up-regulation by STAT3 contributes to mutant KRAS-mediated apoptosis resistance. Such resistance can be overcome by potent BIM induction and concurrent BCL-XL antagonism to enable a synergistic apoptotic response.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.