Guggulsterone induces apoptosis and inhibits lysosomal-dependent migration in human bladder cancer cells.
BACKGROUND
The survival rate and therapeutic options for patients with bladder cancer have improved little in recent decades. Guggulsterone (GS), a phytoestrogen, has been investigated as an anticancer drug in various malignancies.


PURPOSE
The present study aimed to evaluate the anticancer effects of E-isomer and Z-isomer GS in the human bladder cancer cell lines TSGH8301 (low-grade) and T24 (high-grade) and their underlying mechanisms.


METHODS
The cell survival effect of GS was investigated by the MTT and colony formation assays in bladder cancer cell lines. Flow cytometry was used to analyze the cell cycle and cell death. Migration ability was measured by wound healing and transwell assays. Protein expression was determined by Western blot after GS treatment. The potency of GS on subcutaneous TSGH8301 bladder tumors was evaluated using an in vivo imaging system.


RESULTS
E-isomer GS reduced the survival rate of both low- and high-grade human bladder cancer cells. GS caused cell cycle arrest, accompanied by the decrease and increase in cyclin A and p21 levels, respectively. Additionally, caspase-dependent apoptosis was observed following GS treatment. Furthermore, GS treatment downregulated mTOR-Akt signaling and induced autophagy with p62 and LC3β-II expression. Moreover, the farnesoid X receptor was involved in GS-inhibited cell growth. In addition, GS reduced the migration ability with a decrease in integrin-focal adhesion kinase and myosin light chain. Interestingly, the suppression of GS-mediated migration was prevented by the lysosomal inhibitor ammonium chloride (NH4Cl). GS also reduced TSGH8301 bladder cancer cell progression by increasing the level of p21, cleaved caspase 3, cleaved poly (ADP-ribose) polymerase (PARP), and LC3β-II in vivo.


CONCLUSIONS
The current findings suggest that GS treatment may serve as a potential anticancer therapy for different grades of urothelial carcinoma.
['Chen|Ying|Y|', 'Wang|Hisao-Hsien|HH|', 'Chang|Hsin-Han|HH|', 'Huang|Yun-Hsuan|YH|', 'Wang|Jeffrey R|JR|', 'Changchien|Chih-Ying|CY|', 'Wu|Sheng-Tang|ST|']
D000818:Animals D000972:Antineoplastic Agents, Phytogenic D017209:Apoptosis D001343:Autophagy D053148:Caspase 3 D059447:Cell Cycle Checkpoints D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D002470:Cell Survival D006801:Humans D008247:Lysosomes D008807:Mice, Inbred BALB C D011282:Pregnenediones D058570:TOR Serine-Threonine Kinases D001749:Urinary Bladder Neoplasms D023041:Xenograft Model Antitumor Assays
Guggulsterone Apoptosis Migration Bladder cancer Autophagy