Abstract
The incidence of human urinary bladder cancer increases markedly with age, suggesting a mechanistic connection between aging and bladder carcinogenesis and a potential use of anti-aging agents in bladder cancer chemoprevention. Rhodiola rosea, growing in high altitude or cold regions of the world, has been reported to have anti-aging effects in Drosophila. We demonstrated that a R. rosea extract and one of its bioactive components, salidroside, inhibited the growth of bladder cancer cell lines with a minimal effect on nonmalignant bladder epithelial cells TEU-2. Interestingly, the R. rosea extract and salidroside component exhibited a selective ability to inhibit the growth of p53 knockout primary mouse embryo fibroblasts (p53-/- MEFs) compared to their wild-type counterparts. The growth inhibitory effects of the R. rosea extract and salidroside were, however, attenuated in TSC2 and p53 double knock MEFs (TSC2-/-, p53-/- MEFs), suggesting that TSC2 protein is, at least in part, required for the growth inhibitory effects of the R. rosea extract and salidroside. The R. rosea extract and salidroside treatment of UMUC3 cells resulted in an increase of AMP-activated protein kinase (AMPK)-α phosphorylation and a decrease of 4E-BP1 phosphorylation, leading to increased binding of 4E-BP1 to m7 GTP. These results indicate that the R. rosea extract and salidroside inhibit translation initiation. Furthermore, both the R. rosea extract and salidroside treatment of UMUC3 cells caused a significant percentage of cells undergoing autophagy. Therefore, the R. rosea extract and salidroside deserve further study as novel agents for chemoprevention of bladder carcinogenesis.
Highlights
Bladder cancer arises most commonly in the elderly with over 71% of first diagnoses and 85.5% of deaths occurring in patients older than 65 years old [1,2]
We examined the effect of the R. rosea extract, known as SHR-5, and one of its chemical component salidroside on the growth of cancer cell lines derived from different stages of human urinary bladder cancer and on the mTOR pathway, a conserved longevity pathway
To examine the potential anti-bladder cancer effects of SHR-5, human papillary (RT4) and muscle-invasive (T24, UMUC3, J82 and 5637) bladder cancer cell lines, as well as a non-malignant human bladder epithelial TEU-2 cell line were treated with different doses of SHR-5
Summary
Bladder cancer arises most commonly in the elderly with over 71% of first diagnoses and 85.5% of deaths occurring in patients older than 65 years old [1,2]. Long-term calorie restriction (CR) without malnutrition and inhibition of the activity of nutrient-sensing pathways (insulin/IGF-1/mTOR signaling pathways) by mutations or chemical inhibitors consistently and robustly delay aging and extends life span in diverse species [4,5,6,7,8]. Both CR and decreased nutrient-sensing pathway activity can delay the onset of age-related diseases, including diabetes, cancer, cardiovascular disease and brain atrophy [4,5,6,7,8]. Since the mTOR pathway is one of the most commonly deregulated pathways in human urinary bladder cancer through Ras oncogene activation or via gene mutations in PIK3CA, TSC1/2, and PTEN [10,11,12,13,14], agents that have anti-aging properties by targeting the mTOR pathway could be ideal candidates for bladder cancer chemoprevention
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