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Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer.

ABSTRACT: Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells. Riluzole can lead to further decrease in NAD+ (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD+ re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.

SUBMITTER: Wangpaichitr M

PROVIDER: S-EPMC5564767 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer.

Wangpaichitr Medhi M Wu Chunjing C Li Ying Ying YY Nguyen Dan J M DJM Kandemir Hande H Shah Sumedh S Chen Shumei S Feun Lynn G LG Prince Jeffrey S JS Kuo Macus T MT Savaraj Niramol N

Oncotarget 20170701 30

Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. ...[more]

PMID: 28525376

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Project description:ObjectiveTumor drug resistance is a vital obstacle to chemotherapy in lung cancer. Methionine adenosyltransferase 2A has been considered as a potential target for lung cancer treatment because targeting it can disrupt the tumorigenicity of lung tumor-initiating cells. In this study, we primarily observed the role of methionine metabolism in cisplatin-resistant lung cancer cells and the functional mechanism of MAT2A related to cisplatin resistance.Materials and methodsIn this experimental study, we assessed the half maximal inhibitory concentration (IC50) of cisplatin in different cell lines and cell viability via Cell Counting Kit-8. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of relative proteins and genes. Crystal violet staining was used to investigate cell proliferation. Additionally, we explored the transcriptional changes in lung cancer cells via RNA-seq.ResultsWe found H460/DDP and PC-9 cells were more resistant to cisplatin than H460, and MAT2A was overexpressed in cisplatin-resistant cells. Interestingly, methionine deficiency enhanced the inhibitory effect of cisplatin on cell activity and the pro-apoptotic effect. Targeting MAT2A not only restrained cell viability and proliferation, but also contributed to sensitivity of H460/DDP to cisplatin. Furthermore, 4283 up-regulated and 5841 down-regulated genes were detected in H460/DDP compared with H460, and 71 signal pathways were significantly enriched. After treating H460/DDP cells with PF9366, 326 genes were up-regulated, 1093 genes were down-regulated, and 13 signaling pathways were significantly enriched. In TNF signaling pathway, CAS7 and CAS8 were decreased in H460/DDP cells, which increased by PF9366 treatment. Finally, the global histone methylation (H3K4me3, H3K9me2, H3K27me3, H3K36me3) was reduced under methionine deficiency conditions, while H3K9me2 and H3K36me3 were decreased specially via PF9366.ConclusionMethionine deficiency or MAT2A inhibition may modulate genes expression associated with apoptosis, DNA repair and TNF signaling pathways by regulating histone methylation, thus promoting the sensitivity of lung cancer cells to cisplatin.

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Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer.

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Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer.

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