The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model - PubMed (original) (raw)
The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model
Zhongbo Liu et al. Cancers (Basel). 2023.
Erratum in
- Correction: Liu et al. The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model. Cancers 2023, 15, 3086.
Liu Z, Yokoyama NN, Song L, Xie J, Sadeghi Z, Wu YX, Yee S, Wu XR, Wang B, Uchio E, Zi X. Liu Z, et al. Cancers (Basel). 2025 Dec 11;17(24):3954. doi: 10.3390/cancers17243954. Cancers (Basel). 2025. PMID: 41463287 Free PMC article.
Abstract
Background: SHR-5 has been used as an "adaptogen" for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. Methods: UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses. Results: Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p < 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism. Conclusions: Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts' action.
Keywords: bladder cancer chemoprevention; mTOR; metabolism; rhodiola.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Figure 1
SHR-5 drinking increases the survival of the UPII-Ha-ras transgenic mice. (A) Upper panel: genotyping by Southern blotting analysis of NcoI-digested mouse tail DNAs shows wild-type mice with the endogenous UPII fragment, heterozygous mice with Ras/UPII ratio of about 1:2, and homozygous mice with Ras/UPII ratio of about 1:1. Lower panel: Western blotting analysis of Ras expression in the urothelial tissues of wild-type and homozygous mice. (B) Survival curves of male homozygous UPII-mutant Ha-ras transgenic mice that drank regular water (vehicle control) or 1.25 or 6.25 mg/mL SHR-5-supplemented water until 180 days of age. (C) The mean body weight was documented every two weeks. (D) Ratios of organ weights to body weights at the end of the experiment of male UPII-mutant Ha-ras mice fed with indicated drinks as shown in the figure. Error bars: standard deviation. “*” indicates p < 0.05.
Figure 2
The effect of SHR-5 drinking on bladder and ureter weights of UPII-mutant Ha-ras transgenic mice. (A,B) Bladder and ureter weights of male homozygous UPII-mutant Ha-ras transgenic mice that were fed with regular water or water containing 1.25 or 6.25 mg/mL SHR-5 until 180 days of age. (C) Macroscopical examination of bladders, ureters, and kidneys after the transgenic mice were fed with regular water or water containing 1.25 or 6.25 mg/mL SHR-5 until 180 days of age. (D) Average daily water consumption of the mice in indicated treatment groups over time. Error bars represent standard deviation.
Figure 3
The effect of SHR-5 drinking on pathological progression from hyperplasia to papilloma and UCC. (A) H&E images of bladders and ureters from the male UPII-mutant Ha-ras mice after drinking with normal water or SHR-5-containing water for five months. The same control group was used as described in a previously published paper by Liu et al. [13]. Magnification: 100×. (B) Percentages of papillary hyperplasia, nodular hyperplasia, papilloma, and papillary carcinoma of the mice in indicated treatment groups. (C) Simple graphic presentation of the SHR-5’s effects on papillary UCC development in the male UPII-mutant Ha-ras mice.
Figure 4
The effects of SHR-5 drinking on uropathy. (A) Percentages of mice with hydronephrosis in different treatment groups. (B) Six-month-old UPII-Ha-ras mice that drank normal water (control) showed enlarged kidneys, dilated tubular structures, and ureter, whereas age-matched H-ras mice that drank SHR-5 daily showed relatively normal kidneys and no dilation of the ureter. (C) SHR-5 drinking decreased blood urine in UPII-mutant Ha-ras mice. Urine was collected from the mutant Ha-ras mice and examined by urinalysis test strips.
Figure 5
SHR-5 and salidroside inhibit the mTOR pathway. (A) Protein lysates were freshly prepared from bladder urothelial tissues from the mice fed with normal drinking water (control), or indicated concentrations of SHR-5, for 5 months. Western blotting analysis was performed to determine the protein levels of TSC2, phospo-mTOR, 4E-BP1, and phosphor-rpS6. Tubulin served as a loading control. (B,C) IHC-stained tissue sections by anti-Ki67, phospho-MAPK Antibody, and P27 antibodies, respectively, were photographed at ×100 magnifications, and the quantification of percentages of the positively staining cells in each field in treated tumors by normal drinking water, or indicated concentrations of SHR-5, was shown. The same control group was used as described in a previously published paper by Liu et al. [13]. * p < 0.05 and ** p < 0.01.
Figure 6
SHR-5 drinking alters tumor metabolism. Global metabolism profiling using UHPLC/MS/MS, in both positive and negative ion mode, and GC/MS methods were performed on bladder tissues from the UPII-mutant Ha-ras mice (n = 7/treatment group) drinking normal water or SHR-5-containing water at indicated concentrations for five months. (A) Representative metabolites in bladder tumor tissues with dose-dependent and statistically significant alterations by SHR-5 drinking (ps < 0.05). The data are presented as a fold change in the SHR-5 drinking relative to the regular water drinking. (B,C) Significantly enriched metabolic pathways in bladder tumor tissues, which were associated with SHR-5 drinking (p ≤ 0.05), are shown.
References
- Bladder Cancer Key Statistics. [(accessed on 14 April 2023)]. Available online: https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html.
- Kelly G.S. Rhodiola rosea: A possible plant adaptogen. Altern. Med. Rev. 2001;6:293–302. -PubMed
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