Proteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer

Cron, Kyle R.; Zhu, Kaya; Kushwaha, Deepa; Hsieh, Grace; Merzon, Dmitry; Rameseder, Jonathan; Chen, Clark C.; D’Andrea, Alan D.; Kozono, David

doi:10.1371/journal.pone.0073710

Cited by 53 publications

(46 citation statements)

References 48 publications

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“…Recently, proteasome inhibition has been demonstrated to induce apoptosis through the ER stress pathway in pancreatic cancer cells [45]. Moreover, proteasome inhibition was recommended as a promising strategy for radiosensitization of lung cancer via inhibition of NF-κB-mediated expression of DNA repair genes [46]. Thus, proteasome inhibitors hold potential to serve as efficient radiosensitizers and may work to increase the cure rate of various cancers.…”

Section: Discussionmentioning

confidence: 99%

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

Chiu

Lin

et al. 2015

Cancer Letters

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Section: Discussionmentioning

confidence: 99%

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

Chiu

Lin

et al. 2015

Cancer Letters

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“…These two lines were selected because they share common genetic features, e.g. both the two cell lines are wild-type in TP53 and therefore, compared to the mutated lines, they are less likely to exhibit genomic instability over the course of lncRNA screening (18). Another reason is that they exhibit markedly different responses to IR (19).…”

Section: Methodsmentioning

confidence: 99%

Long non‑coding RNA GAS5 increases the radiosensitivity of A549 cells through interaction with the miR‑21/PTEN/Akt axis

et al. 2020

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Radioresistance hinders the therapeutic outcomes of radiotherapy in non-small cell lung cancer (NSCLC). Although long non-coding RNAs (lncRNAs) have been demonstrated to participate in the regulation of multiple cell behaviors, whether they can modulate the radiosensitivity of NSCLC and the underlying molecular mechanisms have not been well investigated. In the present study, it was revealed that NSCLC NCI-H460 cells were more sensitive to ionizing radiation (IR) than A549 cells. Using the RNA-Seq method, four highly differentially expressed lncRNAs were identified, including the growth arrest-specific transcript 5 (GAS5), syntaxin binding protein 5 antisense RNA 1 (STXBP5-AS1), metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and X-inactive specific transcript (XIST), which were predicted to play roles in the acquisition of radiosensitivity. Using real-time quantitative PCR (qPCR), it was demonstrated that lncRNA GAS5 was significantly upregulated in NCI-H460 cells but not in A549 cells during IR. Mechanistically, it was demonstrated that overexpression of lncRNA GAS5 decreased the level of microRNA-21 (miR-21). Overexpression of lncRNA GAS5 or suppression of miR-21 markedly increased the IR-induced cell apoptosis of A549 cells. It was also demonstrated that overexpression of lncRNA GAS5 increased PTEN expression and suppressed Akt phosphorylation through the modulation of miR-21. Notably, it was revealed that IR enhanced the interaction between lncRNA GAS5 and the miR-21/PTEN/Akt axis. In summary, the present findings revealed that lncRNA GAS5 has a radiosensitization effect on NSCLC, indicating the potential application of lncRNA GAS5 in NSCLC radiotherapy.

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“…Scoring was performed as described previously [47]. Briefly, the mean log2 (Cy3/Cy5) ratio was determined for each shRNA sequence using triplicate data.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

et al. 2014

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Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.

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Proteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer

Cited by 53 publications

References 48 publications

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

Long non‑coding RNA GAS5 increases the radiosensitivity of A549 cells through interaction with the miR‑21/PTEN/Akt axis

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

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