ArticleMolecular cancer therapeutics2013
Plk1 phosphorylation of orc2 and hbo1 contributes to gemcitabine resistance in pancreatic cancer.
Article in Molecular cancer therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 109 citations in OpenAlex.
- Preclinical Evaluation of Combined Polo-like Kinase 1 Inhibition and Navitoclax in Experimental Models of Lung Cancer.International journal of molecular sciences · 2026Article
- ATR-dependent phosphorylation of the histone acetyltransferase HBO1 suppresses chromatin binding and promotes replication stress responses.The Journal of biological chemistry · 2026Article
- Large-scale, spatially resolved panoramic CRISPR screening in native tissue environments using Perturb-DBiT.Nature biotechnology · 2026Article
- Histone acetyltransferase HBO1 in cancer biology: Essential mechanisms and implications for targeted therapeutics.Biochimica et biophysica acta. Reviews on cancer · 2026Review
- Origin recognition complex subunit 1 functions as an oncogenic driver and therapeutic target in cancer.Discover oncology · 2025Review
- High-throughput virtual screening, identification andJournal of enzyme inhibition and medicinal chemistry · 2025Article
- HBO1 determines epithelial-mesenchymal transition and promotes immunotherapy resistance in ovarian cancer cells.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Review
- MLN0905 effectively kills gemcitabine-resistant pancreatic cancer cells by targeting PLK1.European journal of medical research · 2025Article
- Multi-Omic Evaluation of PLK1 Inhibitor-Onvansertib-In Colorectal Cancer Spheroids.Journal of mass spectrometry : JMS · 2025Article
- Competitive antagonism of KAT7 crotonylation against acetylation affects procentriole formation and colorectal tumorigenesis.Nature communications · 2025Article
- Spatially ResolvedbioRxiv : the preprint server for biology · 2024Article
- Targeting ABC transporters in PDAC - past, present, or future?Oncotarget · 2024Article
- HBO1 determines SMAD action in pluripotency and mesendoderm specification.Nucleic acids research · 2024Article
- ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells.Journal of experimental & clinical cancer research : CR · 2024Article
- Research progress on antitumor mechanisms and molecular targets of Inula sesquiterpene lactones.Chinese medicine · 2023Review
- TPX2 expression as a negative predictor of gemcitabine efficacy in pancreatic cancer.British journal of cancer · 2023Article
- Post-translational modifications of histones: Mechanisms, biological functions, and therapeutic targets.MedComm · 2023Review
- Systemic analysis of the DNA replication regulator origin recognition complex in lung adenocarcinomas identifies prognostic and expression significance.Cancer medicine · 2023Article
- Targeting Plk1 Sensitizes Pancreatic Cancer to Immune Checkpoint Therapy.Cancer research · 2022Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Although gemcitabine is the standard chemotherapeutic drug for treatment of pancreatic cancer, almost all patients eventually develop resistance to this agent. Previous studies identified Polo-like kinase 1 (Plk1) as the mediator of gemcitabine resistance, but the molecular mechanism remains unknown. In this study, we show that Plk1 phosphorylation of Orc2 and Hbo1 mediates the resistance to gemcitabine. We show that the level of Plk1 expression positively correlates with gemcitabine resistance, both in pancreatic cancer cells and xenograft tumors. Overexpression of Plk1 increases gemcitabine resistance, while inhibition of Plk1 sensitizes pancreatic cancer cells to gemcitabine treatment. To validate our findings, we show that inhibition of Plk1 sensitizes tumors to gemcitabine treatment in a mouse xenograft study. Mechanistically, we find that Plk1 phosphorylation of Orc2 maintains DNA replication on gemcitabine treatment. Furthermore, Plk1 phosphorylation of Hbo1 transcriptionally increases cFos expression and consequently elevates its target multidrug resistance 1 (MDR1), which was previously reported to confer chemotherapeutic drug resistance. Knockdown of cFos or MDR1 sensitizes gemcitabine-resistant cells to gemcitabine treatment. Finally, pancreatic cancer cells expressing Plk1-unphosphorylatable mutants of Orc2 or Hbo1 are more sensitive to gemcitabine than cells expressing wild-type Orc2 or Hbo1. In short, our study provides a mechanism for Plk1-mediated gemcitabine resistance, suggesting that Plk1 is a promising target for treatment of gemcitabine-resistant pancreatic cancer.
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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.