NOX4 Functions as a Mitochondrial Energetic Sensor Coupling Cancer Metabolic Reprogramming to Drug Resistance

Shanmugasundaram K, et al., 8(1):997, Nat Commun., 2017

Reported herein is an analysis of the functional interconnections between the ATP-binding motif within the NADPH oxidase isoform (NOX4), metabolic reprogramming, and cancer drug-resistance using VHL-deficient human-renal carcinoma cells as a model system. Renal cell carcinoma is caused by a mutation or absence of the von Hippel-Lindau (VHL) tumor suppressor gene. The binding affinities of WTNOX4 and mutNOX4 to ATP were studied by surface plasmon resonance (SPR) using a Pall ForteBio Pioneer system equipped with a HisCap sensor chip. The sensor chip surface was activated using nickel ions and NHS/EDC. Subsequently, the protein (wild-type or mutant) was injected over activated surface until the maximal loading is achieved. Any residual active sites on the sensor chip surface was deactivated by injecting ethanolamine. A dilution series of ATP samples were injected using the FastStep injection mode (discontinued). Overall results of this investigation demonstrate that NOX4 functions as a mitochondrial energetic sensor that couple the metabolic switch to cancer cell survival and provide useful insights to understand drug-resistance in glycolytic cancers.

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