Abstract | BACKGROUND: METHODS: Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. RESULTS: Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. CONCLUSION:
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Authors | Stuart R Pierce, Ziwei Fang, Yajie Yin, Lindsay West, Majdouline Asher, Tianran Hao, Xin Zhang, Katherine Tucker, Allison Staley, Yali Fan, Wenchuan Sun, Dominic T Moore, Chang Xu, Yi-Hsuan Tsai, Joel Parker, Varun Vijay Prabhu, Joshua E Allen, Douglas Lee, Chunxiao Zhou, Victoria Bae-Jump |
Journal | Journal of experimental & clinical cancer research : CR
(J Exp Clin Cancer Res)
Vol. 40
Issue 1
Pg. 61
(Feb 08 2021)
ISSN: 1756-9966 [Electronic] England |
PMID | 33557912
(Publication Type: Journal Article)
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Topics |
- Animals
- Cell Proliferation
- Disease Models, Animal
- Endometrial Neoplasms
(drug therapy)
- Female
- Humans
- Mice
- Mice, Transgenic
- Neoplasm Invasiveness
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