NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells

Ma, Chunshuang; Lv, Qian-Ming; Zhang, Keren; Tang, Ya‐Bin; Zhang, Yufei; Shen, Ying; Lei, Hui‐Min; Zhu, Liang

doi:10.1038/s41401-020-0443-1

Cited by 76 publications

(47 citation statements)

References 32 publications

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“…Anti-tumor compounds such as ailanthone [83] and kaempferol [84] decrease Nrf2 expression in promoting oxidative damage and ROS levels as well as triggering apoptosis, leading to enhanced cancer sensitivity to chemotherapy. Overall, studies are in agreement with the fact that Nrf2 activation induces chemoresistance [85] and its inhibition can be considered as an ideal strategy in reversing drug resistance.…”

Section: Nrf2 In Protection and Chemoresistancesupporting

confidence: 81%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

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Section: Nrf2 In Protection and Chemoresistancesupporting

confidence: 81%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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“…The apoptosis rate of sh-GPX4-treated cells was clearly increased, the levels of Ki-67 and PCNA were decreased, and the levels of Cleaved caspase-3 and Cleaved caspase-9 were increased. Similarly, in resistant cells overexpressing GPX4, GPX4 inhibitor overcomes resistance to erlotinib, and knockdown of GPX4 inhibits the migration of resistant cells ( 35 ). Decreased protein level of GPX4 is accompanied with increased levels of cleaved caspase 3 and iron concentrations ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

et al. 2020

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Gefitinib resistance in triple negative breast cancer (TNBC) is a growing important concern. Glutathione peroxidase 4 (GPX4) is a main regulator of ferroptosis, which is pivotal for TNBC cell growth. We investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC. Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected to evaluate tumor growth, apoptosis, and Ki-67 expression. GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability was increased, the limitation of colony formation ability was reduced, apoptosis rate was increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA and ROS production were increased, while GSH was decreased. Silencing GPX4 promoted ferroptosis. Inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also revealed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis. Overall, inhibition of GPX4 stimulated ferroptosis and enhanced TNBC cell sensitivity to gefitinib.

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“…Cell lines which are resistant to erlotinib (HCC827ER), gefitinib (HCC827GR), and osimertinib (HCC827OR and H1975OR1–5) were established, maintained, and authenticated as schematized (Supplementary Fig. 1A) and previously described (9–11). The cells were cultured in RPMI 1640 medium (Gibco, USA) containing 10% FBS, 1% GlutaMAX, and 1% penicillin-streptomycin at 37 °C with 5% CO2.…”

Section: Methodsmentioning

confidence: 99%

“…Resistance is one of the biggest challenges for cancer treatment (8). Based on our in vitro and in vivo cancer targeted therapy resistance models (9–11), we repeatedly and curiously noticed that an activated rather than suppressed status was achieved in cGAS-STING signaling when these cancer cells acquired resistance to therapeutic drugs. We hypothesized that the cells that can upregulate cGAS-STING signaling would acquire the ability to cope with drug stress and evolve drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Cancer cell-autonomous cGAS-STING response confers drug resistance

Wang

Lei

et al. 2021

Preprint

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As an evolutionarily conserved DNA-sensing machinery in innate immunity, the cGAS-STING pathway has been reported to play an important role in immune surveillance and tumor suppression. Recent evidence suggests an intriguing tumor- and metastasis-promoting effect of this signaling pathway, either in a cancer cell-autonomous or a cancer cell-nonautonomous, bystander cell-mediated manner. Here, we show a new face of cGAS-STING signaling whose activation in a cancer-cell-autonomous response manner confers drug resistance. Targeted or conventional chemotherapy drug treatment induced cancer cell cytosolic DNA accumulation and triggered subsequent cGAS-STING signaling activation in cancer cell lines and the human cell-derived xenograft tumors. This activation promoted an acquisition and maintenance of drug resistance which was prevented and overcome in vitro and in vivo by blockade of STING signaling. This finding highlights a new face of cGAS-STING signaling and an ability of cancer cells to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress and warrants a caution in combining STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.

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NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells

Cited by 76 publications

References 32 publications

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

Cancer cell-autonomous cGAS-STING response confers drug resistance

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