ArticleCell death & disease2013
Chemotherapy-mediated p53-dependent DNA damage response in clear cell renal cell carcinoma: role of the mTORC1/2 and hypoxia-inducible factor pathways.
Article in Cell death & disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- DEL-1 is an Endogenous Senolytic Protein that Inhibits Senescence-Associated Bone Loss.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma.Cell death discovery · 2025Review
- Identifying potential risk genes for clear cell renal cell carcinoma with deep reinforcement learning.Nature communications · 2025Article
- Loss of SETD2 in wild-type VHL clear cell renal cell carcinoma sensitizes cells to STF-62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis.Molecular oncology · 2025Article
- Establishment and Characterization of Multi-Drug Resistant p53-Negative Osteosarcoma SaOS-2 Subline.Diagnostics (Basel, Switzerland) · 2023Article
- A novel germline gain-of-function HIF2A mutation in hepatocellular carcinoma with polycythemia.Aging · 2020Article
- Therapy-Induced Senescence Drives Bone Loss.Cancer research · 2020Article
- Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.Cell metabolism · 2018Article
- Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis.Cell death and differentiation · 2017Article
- VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma.Oncotarget · 2017Article
- HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma.BMC cancer · 2016Article
- p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines.Cancer chemotherapy and pharmacology · 2016Article
- ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
- Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma.Cancer letters · 2015Article
- DNA damage-induced S and G2/M cell cycle arrest requires mTORC2-dependent regulation of Chk1.Oncotarget · 2015Article
- Role of mTOR-Chk1 in enhancing DNA-damaging therapy.Cell cycle (Georgetown, Tex.) · 2015Article
- TAp73 promotes anabolism.Oncotarget · 2014Article
- Article
- Review
- The induction of thioredoxin-1 by epinephrine withdraws stress via interaction with β-arrestin-1.Cell cycle (Georgetown, Tex.) · 2014Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The DNA-damaging agent camptothecin (CPT) and its analogs demonstrate clinical utility for the treatment of advanced solid tumors, and CPT-based nanopharmaceuticals are currently in clinical trials for advanced kidney cancer; however, little is known regarding the effects of CPT on hypoxia-inducible factor-2α (HIF-2α) accumulation and activity in clear cell renal cell carcinoma (ccRCC). Here we assessed the effects of CPT on the HIF/p53 pathway. CPT demonstrated striking inhibition of both HIF-1α and HIF-2α accumulation in von Hippel-Lindau (VHL)-defective ccRCC cells, but surprisingly failed to inhibit protein levels of HIF-2α-dependent target genes (VEGF, PAI-1, ET-1, cyclin D1). Instead, CPT induced DNA damage-dependent apoptosis that was augmented in the presence of pVHL. Further analysis revealed CPT regulated endothelin-1 (ET-1) in a p53-dependent manner: CPT increased ET-1 mRNA abundance in VHL-defective ccRCC cell lines that was significantly augmented in their VHL-expressing counterparts that displayed increased phosphorylation and accumulation of p53; p53 siRNA suppressed CPT-induced increase in ET-1 mRNA, as did an inhibitor of ataxia telangiectasia mutated (ATM) signaling, suggesting a role for ATM-dependent phosphorylation of p53 in the induction of ET-1. Finally, we demonstrate that p53 phosphorylation and accumulation is partially dependent on mTOR activity in ccRCC. Consistent with this result, pharmacological inhibition of mTORC1/2 kinase inhibited CPT-mediated ET-1 upregulation, and p53-dependent responses in ccRCC. Collectively, these data provide mechanistic insight into the action of CPT in ccRCC, identify ET-1 as a p53-regulated gene and demonstrate a requirement of mTOR for p53-mediated responses in this tumor type.
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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.