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

Ziyi Zhao; Jiandong Wang; Weimin Kong; Ziwei Fang; Michael F Coleman; Ginger L Milne; Wesley C Burkett; Meredith A Newton; Olivia Lara; Douglas Lee; Boer Deng; Xiaochang Shen; Hongyan Suo; Wenchuan Sun; Stephen D Hursting; Chunxiao Zhou; Victoria L Bae-Jump

doi:10.1016/j.ygyno.2024.04.012

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

Gynecol Oncol. 2024 Apr 25:186:126-136. doi: 10.1016/j.ygyno.2024.04.012. Online ahead of print.

Authors

Ziyi Zhao¹, Jiandong Wang², Weimin Kong², Ziwei Fang¹, Michael F Coleman³, Ginger L Milne⁴, Wesley C Burkett⁵, Meredith A Newton⁵, Olivia Lara⁵, Douglas Lee⁶, Boer Deng¹, Xiaochang Shen¹, Hongyan Suo¹, Wenchuan Sun⁵, Stephen D Hursting³, Chunxiao Zhou⁷, Victoria L Bae-Jump⁸

Affiliations

¹ Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100006, PR China; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100006, PR China.
³ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁵ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Omic Insight, Durham, NC 27710, USA.
⁷ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: czhou@med.unc.edu.
⁸ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

PMID: 38669767
DOI: 10.1016/j.ygyno.2024.04.012

Abstract

Objective: Overweight/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 benefits 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.

Methods: Lkb1^fl/flp53^fl/fl mice were fed HFD or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on a HFD or switched to a LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial cancer, 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.

Results: HFD-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.

Conclusion: In Lkb1^fl/flp53^fl/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 an EC prevention and treatment strategies in overweight/obesity women.

Keywords: Gene expression; Intermittent energy restriction (IER); Metabolites; Paclitaxel; Tumor growth.