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Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time.

ABSTRACT: Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.

SUBMITTER: Xu T

PROVIDER: S-EPMC8976067 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time.

Xu Tong T Junge Jason A JA Delfarah Alireza A Lu Yi-Tsung YT Arnesano Cosimo C Iqbal Maheen M Delijani Kevin K Hsieh Tien-Chan TC Hodara Emmanuelle E Mehta Hemal H HH Cohen Pinchas P Graham Nicholas A NA Fraser Scott E SE Goldkorn Amir A

Scientific reports 20220401 1

Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitoch ...[more]

PMID: 35365706

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Project description:ObjectiveRedox adaptation plays a critical role in cancer cells' drug tolerance and sensitivity. The antioxidative response is induced by nuclear factor erythroid 2-related factor 2 (Nrf2), which triggers the transcriptional activation of genes related to chemosensitivity, glutathione synthesis, and cell protection. Although Nestin1 is known to regulate cellular redox homeostasis by regulating Nrf2 in lung cancer cells, its regulatory effect on the antioxidative state of bladder cancer (BC) cells remains unclear.MethodsThe oxidative stress levels in two cisplatin-treated BC cell lines (T24 and J82) were examined using 2',7'-dichlorofluorescin diacetate staining and real-time quantitative reverse transcription-PCR (RT-qPCR) assays. The cell viability, growth, and apoptosis were determined using CCK-8, colony formation, and flow cytometric assays, respectively. The mRNA and protein levels of Nestin1, Nrf2, and several antioxidant enzymes were quantified using RT-qPCR and western blot assays. A mouse xenograft model was used to determine the effect of Nestin1 on the T24 tumor growth in vivo.ResultsCisplatin treatment induced reactive oxygen species (ROS) generation and antioxidative damage in the T24 and J82 cells, reducing their viability and growth and triggering their apoptosis. Moreover, the Nestin1 and Nrf2 protein levels were enhanced in both treated cell lines. Loss- and gain-of-function assays indicated that Nestin1 expression was positively correlated with the Nrf2 protein expression in the BC cells. Nestin1 overexpression reduced the ROS generation, alleviated the redox disorder, promoted cell viability, and reduced apoptosis, but its silencing had the opposite effects. Importantly, Nestin1 overexpression enhanced the chemoresistance of BC cells to cisplatin in vivo, but its knockdown improved the chemosensitivity of the cells and increased their apoptosis.ConclusionThese results provide a theoretical basis for further targeting the transcription factors, including Nestin1 and Nrf2, in the treatment of BC with cisplatin.

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Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time.

Publications

Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time.

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