Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism
UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcin...
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MDPI AG
2023-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/4/1666 |
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| author | Zhongbo Liu Liankun Song Jun Xie Xue-Ru Wu Greg E. Gin Beverly Wang Edward Uchio Xiaolin Zi |
| author_facet | Zhongbo Liu Liankun Song Jun Xie Xue-Ru Wu Greg E. Gin Beverly Wang Edward Uchio Xiaolin Zi |
| author_sort | Zhongbo Liu |
| collection | DOAJ |
| description | UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (<i>p</i> = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (<i>p</i> = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells. |
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| language | English |
| last_indexed | 2024-03-11T08:21:42Z |
| publishDate | 2023-02-01 |
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| series | Molecules |
| spelling | doaj.art-08536ba2771f4d299df8742524daffbf2023-11-16T22:21:37ZengMDPI AGMolecules1420-30492023-02-01284166610.3390/molecules28041666Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer MetabolismZhongbo Liu0Liankun Song1Jun Xie2Xue-Ru Wu3Greg E. Gin4Beverly Wang5Edward Uchio6Xiaolin Zi7Department of Urology, University of California Irvine, Orange, CA 92868, USADepartment of Urology, University of California Irvine, Orange, CA 92868, USADepartment of Urology, University of California Irvine, Orange, CA 92868, USADepartment of Urology, NYU School of Medicine, New York, NY 10016, USADepartment of Urology, University of California Irvine, Orange, CA 92868, USADepartment of Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA 92868, USADepartment of Urology, University of California Irvine, Orange, CA 92868, USADepartment of Urology, University of California Irvine, Orange, CA 92868, USAUPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (<i>p</i> = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (<i>p</i> = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells.https://www.mdpi.com/1420-3049/28/4/1666KawainmTORchemopreventionbladder cancer |
| spellingShingle | Zhongbo Liu Liankun Song Jun Xie Xue-Ru Wu Greg E. Gin Beverly Wang Edward Uchio Xiaolin Zi Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism Molecules Kawain mTOR chemoprevention bladder cancer |
| title | Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism |
| title_full | Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism |
| title_fullStr | Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism |
| title_full_unstemmed | Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism |
| title_short | Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism |
| title_sort | kavalactone kawain impedes urothelial tumorigenesis in upii mutant ha ras mice via inhibition of mtor signaling and alteration of cancer metabolism |
| topic | Kawain mTOR chemoprevention bladder cancer |
| url | https://www.mdpi.com/1420-3049/28/4/1666 |
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