ArticleScientific reports2025
Differential unfolded protein response regulation in KRAS silencing sensitive and innately resistant colorectal cancer cells.
Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.bioRxiv : the preprint server for biology · 2025Article
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9 authors.
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Abstract
Despite the development of mutant-selective KRAS inhibitors, colorectal cancer (CRC) responses remain limited, with stable disease and rapid recurrence being common outcomes. The molecular mechanisms enabling CRC cells to tolerate KRAS inhibition and ultimately develop resistance remain poorly understood. Here, we investigated early transcriptional and proteomic responses to KRAS silencing in 3D CRC cell line spheroid models, aiming to identify pathways associated with sensitivity or resistance to KRAS blockade. Cell lines were stratified into KRAS silencing-sensitive (HCT116 and SW480) and -resistant (LS174T and SW837) groups based on spheroid growth, cell cycle progression, and apoptosis induction. Transcriptional profiling revealed the unfolded protein response (UPR) and WNT/β-catenin signaling as pathways specifically upregulated in KRAS silencing-sensitive cells and downregulated in resistant cells. Proteomic analysis of membrane-enriched fractions further supported UPR deregulation, showing a pronounced downregulation of translation-related proteins in sensitive cells. Functional assays validated that the sensitive cell line HCT116 exhibits reduced protein aggregation and lower translational capacity upon KRAS knockdown, consistent with UPR activation. Pharmacological inhibition of IRE1α-mediated UPR signaling did not revert KRAS silencing-induced cell cycle arrest or apoptosis in this cell line. Collectively, our results highlight the UPR activation as an early adaptive response of KRAS-dependent CRC cells to KRAS silencing.
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