Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer

Zhao, Z.; Wang, J.; Kong, W.; Fang, Z.; Coleman, M.; Milne, G.; Burkett, W. C.; Newton, M. A.; Lee, D.; Deng, B.; Shen, X.; Suo, H.; Sun, W.; Hursting, S.; Zhou, C.; Bae-Jump, V. L.

doi:10.1101/2024.02.02.578679

bioRxiv · 10.1101/2024.02.02.578679

Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer

Zhao, Z.·Wang, J.·Kong, W.·Fang, Z.·Coleman, M.·Milne, G.·Burkett, W. C.·Newton, M. A.·Lee, D.·Deng, B.·Shen, X.·Suo, H.·Sun, W.·Hursting, S.·Zhou, C.·Bae-Jump, V. L.

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Abstract

ObjectiveOverweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential abilities of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. MethodsLkb1fl/flp53fl/fl mice were fed high-fat diet (HFD) or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on HFD or switched to LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial tumor, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. ResultsHFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. ConclusionIn Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as a EC prevention strategy in women with overweight/obesity.

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Zhao, Z., Wang, J., Kong, W., Fang, Z., Coleman, M., Milne, G., Burkett, W. C., Newton, M. A., Lee, D., Deng, B., Shen, X., Suo, H., Sun, W., Hursting, S., Zhou, C., Bae-Jump, V. L.. 2024-02-07. Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer. https://doi.org/10.1101/2024.02.02.578679

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