Journal Article

Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway

Naiki, Taku, Yasui, Takahiro, Takahashi, Satoru, Ando, Ryosuke, Nagai, Takashi, Kawai, Noriyasu, Suzuki, Shugo, Kato, Hiroyuki, Nagayasu, Yuko, Etani, Toshiki, Naiki‐Ito, Aya, Nozaki, Satoshi, Iida, Keitaro

2020

Overview

Luteolin is a natural flavonoid with strong anti–oxidative properties that is reported to have an anti–cancer effect in several malignancies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin‐1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell‐cycle arrest, p21 upregulation and downregulation of phospho(p)‐S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p‐S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BBN)‐induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67‐labeling index and p‐S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin‐3ʹ‐O‐glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin‐3ʹ‐glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product‐derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling. Luteolin suppresses cell proliferation through downregulation of mTOR signaling and upregulation of p21 in bladder cancers both in vitro and in vivo. mTOR activity is correlated with invasive ability in human bladder cancer cases. A metabolite of luteolin decreases cell viability and squamous differentiation in in vivo rat bladder cancer models.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: animal model / Animals / Apoptosis / Apoptosis - drug effects / Bladder cancer / Butylhydroxybutylnitrosamine - toxicity / Cancer / Cancer therapies / Cell cycle / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cell survival / Chemical industry / chemoprevention / Chemotherapy / Cyclin-dependent kinase inhibitor p21 / Disease Models, Animal / Experiments / Flavonoids / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Humans / Intracellular signalling / Ki-67 Antigen - genetics / Kinases / Laboratories / Luteolin - metabolism / Luteolin - pharmacology / Male / Metastasis / Mice / mTOR / Natural products / Oral administration / Original / Oxidative stress / Proteins / Proto-Oncogene Proteins c-akt - genetics / Rapamycin / Rats / Reactive oxygen species / rho GTP-Binding Proteins - genetics / Signal transduction / Signal Transduction - drug effects / Thioredoxin / Thioredoxins - genetics / TOR protein / TOR Serine-Threonine Kinases - genetics / Urinary Bladder Neoplasms - chemically induced / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - pathology / Xenograft Model Antitumor Assays / Xenografts