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HRI Kinase Modulation by BTdCPU as a Therapeutic Strategy for Bortezomib Resistance in Prostate Cancer
Semih Seker1, Emrah Okur2, Azmi Yerlikaya1,3
1Department of Medical Biology, Faculty of Medicine, Kutahya Health Sciences University, Kutahya, Turkey.
Current Medicinal Chemistry
|July 3, 2026
Summary
Heme-Regulated Inhibitor (HRI) kinase activation by BTdCPU may overcome bortezomib resistance in prostate cancer. This pathway modulation shows promise for treating resistant cancers, warranting further investigation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Heme-Regulated Inhibitor (HRI) kinase is crucial for eIF2α phosphorylation and Integrated Stress Signaling (ISR).
- Prostate cancer cells can develop resistance to bortezomib, a proteasome inhibitor.
- Understanding resistance mechanisms is vital for improving cancer therapy.
Purpose of the Study:
- To investigate if pharmacologic modulation of the HRI/ISR pathway with BTdCPU retains activity in bortezomib-resistant prostate cancer cells.
- To explore the relationship between HRI pathway activation and stress-signaling markers in resistant cells.
- To assess the clinical relevance of HRI expression in prostate cancer.
Main Methods:
- Cytotoxicity assays (MTT) to determine IC50 values for BTdCPU and bortezomib in parental and resistant cells.
- Real-time cell monitoring (iCELLigence) and morphology analysis (AO/EB) to assess drug effects.
- Western blotting to evaluate key proteins: HRI, p-eIF2α, Hsp70, Hsp60, and polyubiquitin (PolyUb) conjugates.
- Public-dataset analysis for clinical context on HRI expression.
Main Results:
- Bortezomib-resistant cells exhibited approximately 26-fold higher resistance compared to parental cells.
- BTdCPU demonstrated cytotoxic effects in both cell types, with slightly higher IC50 in resistant cells.
- BTdCPU-induced HRI activation promoted eIF2α phosphorylation independently of Hsp70 and PolyUb accumulation, unlike bortezomib in parental cells.
- Bioinformatic analysis revealed differential HRI expression across prostate cancer subgroups and TP53 status.
Conclusions:
- Cancer cell resistance to bortezomib may involve overactivation of the HRI/eIF2α signaling pathway.
- BTdCPU warrants further investigation as a potential therapeutic strategy to overcome bortezomib resistance.
- The study provides pharmacologic and associative data, highlighting the need for causal investigations into HRI/ISR signaling in resistance.
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