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. 2023 Aug 4:13:1219923.
doi: 10.3389/fonc.2023.1219923. eCollection 2023.

Orlistat exerts anti-obesity and anti-tumorigenic effects in a transgenic mouse model of endometrial cancer

Guangxu Xu  1   2 , Ziyi Zhao  2   3 , Weiya Z Wysham  4 , Dario R Roque  5 , Ziwei Fang  2   3 , Wenchuan Sun  2 , Yajie Yin  2 , Boer Deng  2   3 , Xiaochang Shen  2   3 , Chunxiao Zhou  2   6 , Victoria Bae-Jump  2   6
Affiliations

Orlistat exerts anti-obesity and anti-tumorigenic effects in a transgenic mouse model of endometrial cancer

Guangxu Xu et al. Front Oncol. .

Abstract

Introduction: Among all cancers, endometrial cancer is most strongly associated with obesity, with more than 65% of endometrial cancers attributable to obesity and being overweight. Fatty acid synthase (FAS), a key lipogenic enzyme, is expressed in endometrial cancer tumors and is associated with a worse prognosis for this disease. Orlistat, an FAS inhibitor, is an FDA-approved weight loss medication that has demonstrated anti-tumor activity in a variety of preclinical cancer models.

Methods: In this study, the Lkb1fl/flp53fl/fl mouse model of endometroid endometrial cancer was exposed to three diet interventions, including a high fat diet (obese), a low fat diet (lean) and switch from a high fat to a low fat diet, and then exposed to orlistat or placebo.

Results: The mice fed a high-fat diet had significantly increased body weight and tumor weight compared to mice fed a low-fat diet. Switching from a high-fat diet to a low fat diet led to a reduction in mouse weight and suppressed tumor growth, as compared to both the high fat diet and low fat diet groups. Orlistat effectively decreased body weight in obese mice and inhibited tumor growth in obese, lean, and the high fat diet switch to low fat diet mouse groups through induction of apoptosis. Orlistat also showed anti-proliferative activity in nine of 11 primary cultures of human endometrial cancer.

Discussion: Our findings provide strong evidence that dietary intervention and orlistat have anti-tumor activity in vivo and supports further investigation of orlistat in combination with dietary interventions for the prevention and treatment of endometrial cancer.

Keywords: apoptosis; dietary intervention; endometrial cancer; obesity; orlistat.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Effect of orlistat on body weight in mice fed a HFD or LFD. The Lkb1fl/flp53fl/fl mice fed either a HFD or LFD were divided into six diet/drug intervention groups, and the experimental strategy is shown in (A). The body weights of mice from control and orlistat treatment groups were measured at the end of treatment (B). The average body weight loss in orlistat-treated groups (C). Measurement of fat and lean mass of mice from control and orlistat-treated groups using EchoMRI (D, E). Orlistat reduced the ratio of gonadal fat/body weight in each group (F). H&E staining showed that orlistat decreased the size of gonadal adipocytes in HFD, LFD, and HFD-LFD mice (G). *p< 0.05, **p< 0.01. #Indicates comparison with corresponding control, #p< 0.05, ##p<0.01.
Figure 2
Figure 2
Effect of orlistat on hepatic fat deposition and serum biochemical parameters in HFD, LFD HFD-LFD mice. Serum levels of TG, glucose, insulin, and leptin were significantly elevated in HFD mice compared with LFD and HFD-LFD groups, and treatment of mice with orlistat for four weeks reduced serum TG, glucose, insulin, and leptin productions in the HFD group (A–D). The inflammatory factors IL-6 and TNF-α were elevated in HFD mice, and orlistat treatment significantly decreased serum IL-6 and TNF-α levels in these mice (E, F). The liver weight was significantly increased in mice fed a HFD, and treatment with orlistat for 4 weeks effectively reduced liver weight (G). H&E staining result showed that HFD induced balloon-like structures in liver tissues, and orlistat alleviated those pathologic changes in the livers (H). *p<0.05, **p<0.01. #compared with HFD-fed mice. ##p<0.01.
Figure 3
Figure 3
Orlistat inhibited tumor growth in HFD, LFD and HFD-LFD mice. HFD, LFD and HFD-LFD mice were treated with orlistat at 60 mg/kg for four weeks. Orlistat at 60 and 200 mg/kg effectively inhibited EC tumor growth (A). HFD significantly promoted tumor growth compared to an LFD and HFD-LFD, and orlistat treatment (60 mg/kg) for 4 weeks inhibited tumor growth in HFD, LFD, and HFD-LFD mice (B). The measurements of free fatty acid in tumor tissues in each group (C). The EC tumor tissues in each group were stained with FAS, p-ACC, Ki67, and Bcl-xL. The results showed orlistat significantly reduced the expression of FAS, p-ACC, Ki67, and Bcl-xL in HFD, LFD, and HFD-LFD mice (D–G). *p<0.05, **p<0.01. #Indicates comparison with corresponding control, #p< 0.05, ##p<0.01.
Figure 4
Figure 4
Orlistat reduced angiogenesis in obese and lean mice. The expression of VEGF and MMP-9 were measured by IHC staining in EC tumors of Lkb1fl/flp53fl/fl mice. Orlistat downregulated the expression of VEGF in the HFD and HFD-LFD groups, as well as MMP-9 in all three groups (HFD, LFD and HFD-LFD) (A, B). Orlistat treatment reduced serum VEGF levels in HFD mice (C). Western blotting results demonstrated that orlistat treatment for four weeks also reduced the expression of VEGF and MMP-9 in the EC tumors (D). *p<0.05, **p<0.01. #Indicates comparison with corresponding control, #p< 0.05, ##p<0.01.
Figure 5
Figure 5
Orlistat inhibited cell proliferation in primary cultures of human EC. The effect of orlistat on cell proliferation was detected by MTT assay in 11 primary cultures of human endometrioid ECs (A). Changes of cleaved caspase-3 were measured by ELISA assay in EC1, EC4, EC5, EC6, EC7, and EC8 cells (B). The expression of Bcl-xL in EC1, EC4, and EC7 samples was assessed by western blotting after 24 hours of treatment with orlistat (C).
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