Bortezomib sensitizes esophageal squamous cancer cells to radiotherapy by suppressing the expression of HIF-1α and apoptosis proteins

Wang, Di; Qin, Qin; Qin-juan, Jiang; Wang, Dafei

doi:10.3233/xst-160571

Cited by 15 publications

(17 citation statements)

References 19 publications

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“…Inhibition of HSP90, a key chaperone protein of HIF-1α, overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer 125 . Bortezomib, a reversible proteasome inhibitor, sensitizes esophageal squamous cancer cells to radiotherapy by decreasing HIF-1α and VEGF expression 126 .…”

Section: Interplay Between Mitochondrial Dysfunctions and Hifsmentioning

confidence: 99%

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

et al. 2021

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Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.

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Section: Interplay Between Mitochondrial Dysfunctions and Hifsmentioning

confidence: 99%

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

et al. 2021

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“…Among the wide ranges of potential radiosensitizers investigated, well-recognized reagents includes gold nanoparticles, hypoxia-specific cytotoxins, drugs involved in DNA repair, drugs involved in cell signaling, and growth factors [8]. Experimental and preclinical studies have demonstrated the efficacy of radiosensitizers in improving response to radiation therapy, and several inhibitors have been or are currently being tested as potential radiosensitizers in clinical trials, including poly(ADP-ribose) polymerase inhibitors(PARPi) [9–11], proteasome inhibitors [12–14], and epidermal growth factor receptor inhibitors [15]. Recently some strategies have been investigated as the radiosensitizers for osteosarcoma, histone deacetylase inhibitors (HDACi),DNA-PKcs inhibitors are considered as attractive options for the radiosensitization of this cancer type [16,17].…”

Section: Introductionmentioning

confidence: 99%

Natural product β-thujaplicin inhibits homologous recombination repair and sensitizes cancer cells to radiation therapy

et al. 2017

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Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR)-mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients’ responses to radiation therapy, a mainstay of treatment for many human cancers. In this study, in order to systematically identify natural products with an inhibitory effect on HR repair, we developed a high-throughput image-based HR repair screening assay and screened a chemical library containing natural products. Among the most interesting of the candidate compounds identified from the screen was β-thujaplicin, a bioactive compound isolated from the heart wood of plants in the Cupressaceae family, can significantly inhibit HR repair. We further demonstrated that β-thujaplicin inhibits HR repair by reducing the recruitment of a key HR repair protein, Rad51, to DNA double-strand breaks. More importantly, our results showed that β-thujaplicin can radiosensitize cancer cells. Additionally, β-thujaplicin sensitizes cancer cells to PARP inhibitor in different cancer cell lines. Collectively, our findings for the first time identify natural compound β-thujaplicin, which has a good biosafety profile, as a novel HR repair inhibitor with great potential to be translated into clinical applications as a sensitizer to DNA-damage-inducing treatment such as radiation and PARP inhibitor. In addition, our study provides proof of the principle that our robust high-throughput functional HR repair assay can be used for a large-scale screening system to identify novel natural products that regulate DNA repair and cellular responses to DNA damage-inducing treatments such as radiation therapy.

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“…It regulates hypoxia-inducible factor (HIF) 1 and 2, which in turn can play critical roles in cancer metabolism, stem cell proliferation, maintaining aggressiveness and metastatic potential of both OSCC and OAC cells ( Figure 3 ) ( 119 , 120 ). Overexpression of HIFs also reduces radio-sensitivity ( 121 , 122 ) and induces EMT in cancer cells ( 123 , 124 ). On the other hand, inhibition of HIF1α resulted in suppression of tumorigenicity of OSCC cells in both in vitro and in vivo ( 125 ).…”

Section: Targeting Hypoxia-related Pathways In Esophageal Cancer To Ementioning

confidence: 99%

Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas

et al. 2021

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Cancer stem cells (CSCs) in esophageal cancer have a key role in tumor initiation, progression and therapy resistance. Novel therapeutic strategies to target CSCs are being tested, however, more in-depth research is necessary. Eradication of CSCs can result in successful therapeutic approaches against esophageal cancer. Recent evidence suggests that targeting signaling pathways, miRNA expression profiles and other properties of CSCs are important strategies for cancer therapy. Wnt/β-catenin, Notch, Hedgehog, Hippo and other pathways play crucial roles in proliferation, differentiation, and self-renewal of stem cells as well as of CSCs. All of these pathways have been implicated in the regulation of esophageal CSCs and are potential therapeutic targets. Interference with these pathways or their components using small molecules could have therapeutic benefits. Similarly, miRNAs are able to regulate gene expression in esophageal CSCs, so targeting self-renewal pathways with miRNA could be utilized to as a potential therapeutic option. Moreover, hypoxia plays critical roles in esophageal cancer metabolism, stem cell proliferation, maintaining aggressiveness and in regulating the metastatic potential of cancer cells, therefore, targeting hypoxia factors could also provide effective therapeutic modalities against esophageal CSCs. To conclude, additional study of CSCs in esophageal carcinoma could open promising therapeutic options in esophageal carcinomas by targeting hyper-activated signaling pathways, manipulating miRNA expression and hypoxia mechanisms in esophageal CSCs.

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Bortezomib sensitizes esophageal squamous cancer cells to radiotherapy by suppressing the expression of HIF-1α and apoptosis proteins

Cited by 15 publications

References 19 publications

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

Natural product β-thujaplicin inhibits homologous recombination repair and sensitizes cancer cells to radiation therapy

Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas

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