ArticleMolecular cancer therapeutics2010
Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth.
Article in Molecular cancer therapeutics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 214 papers.
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214 citing papers in PubMed, 372 citations in OpenAlex.
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- Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis.Acta pharmacologica Sinica · 2024Article
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- Molecular panorama of therapy resistance in prostate cancer: a pre-clinical and bioinformatics analysis for clinical translation.Cancer metastasis reviews · 2024Review
- ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2.The Journal of clinical investigation · 2024Article
- Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer.Frontiers in oncology · 2024Review
- The Growth Inhibitory Effect of Resveratrol and Gallic Acid on Prostate Cancer Cell Lines through the Alteration of Oxidative Stress Balance: The Interplay betweenAnti-cancer agents in medicinal chemistry · 2024Article
- Mini-review: research and progress of oxeiptosis in diseases.Frontiers in cell and developmental biology · 2024Review
- Nrf2-Mediated Antioxidant Response and Drug Efflux Transporters Upregulation as Possible Mechanisms of Resistance in Photodynamic Therapy of Cancers.OncoTargets and therapy · 2024Review
154 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Loss-of-function mutations in the nuclear factor erythroid-2-related factor 2 (Nrf2) inhibitor Kelch-like ECH-associated protein 1 (Keap1) result in increased Nrf2 activity in non-small cell lung cancer and confer therapeutic resistance. We detected point mutations in Keap1 gene, leading to nonconservative amino acid substitutions in prostate cancer cells. We found novel transcriptional and posttranscriptional mechanisms of Keap1 inactivation, such as promoter CpG island hypermethylation and aberrant splicing of Keap1, in DU-145 cells. Very low levels of Keap1 mRNA were detected in DU-145 cells, which significantly increased by treatment with DNA methyltransferase inhibitor 5-aza-deoxycytidine. The loss of Keap1 function led to an enhanced activity of Nrf2 and its downstream electrophile/drug detoxification pathway. Inhibition of Nrf2 expression in DU-145 cells by RNA interference attenuated the expression of glutathione, thioredoxin, and the drug efflux pathways involved in counteracting electrophiles, oxidative stress, and detoxification of a broad spectrum of drugs. DU-145 cells constitutively expressing Nrf2 short hairpin RNA had lower levels of total glutathione and higher levels of intracellular reactive oxygen species. Attenuation of Nrf2 function in DU-145 cells enhanced sensitivity to chemotherapeutic drugs and radiation-induced cell death. In addition, inhibition of Nrf2 greatly suppressed in vitro and in vivo tumor growth of DU-145 prostate cancer cells. Thus, targeting the Nrf2 pathway in prostate cancer cells may provide a novel strategy to enhance chemotherapy and radiotherapy responsiveness and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes.
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