Stellettin B Induces Cell Death in Bladder Cancer Via Activating the Autophagy/DAPK2/Apoptosis Signaling Cascade

• Published in: Marine drugs Vol. 21; no. 2; p. 73
• Main Authors: Chang, Chun-Han, Lin, Bo-Jyun, Chen, Chun-Han, Nguyen, Nham-Linh, Hsieh, Tsung-Han, Su, Jui-Hsin, Chen, Mei-Chuan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.01.2023; MDPI
• Subjects: AKT protein; Animals; Annexin V; Anticancer properties; Antitumor activity; Apoptosis; Autophagy; Bladder; Bladder cancer; Cancer; Cancer therapies; Care and treatment; Caspase-3; Cell cycle; Cell death; Cell Line, Tumor; Cell viability; Cells; Chemotherapy; Clinical trials; Cytotoxicity; DAPK2; Death-Associated Protein Kinases; Development and progression; Drugs; Fibroblast growth factor receptors; Gene expression; Health aspects; Immunotherapy; Kinases; Marine invertebrates; Metastasis; Monoclonal antibodies; mRNA; Natural products; Patient outcomes; Phosphorylation; Porifera - metabolism; Protein arrays; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Relapse; Signaling; stellettin B; Surgery; Survival; TOR protein; Toxicity; Triterpenes - pharmacology; Tumors; Urinary Bladder Neoplasms - drug therapy; Western blotting; Taiwan; apoptosis; stellettin B; autophagy; DAPK2; bladder cancer
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md21020073

Bladder cancer (BC) is one of the most prevalent cancers worldwide. However, the recurrence rate and five-year survival rate have not been significantly improved in advanced BC, and new therapeutic strategies are urgently needed. The anticancer activity of stellettin B (SP-2), a triterpene isolated from the marine sponge sp., was evaluated with the MTT assay as well as PI and Annexin V/7-AAD staining. Detailed mechanisms were elucidated through an NGS analysis, protein arrays, and Western blotting. SP-2 suppressed the viability of BC cells without severe toxicity towards normal uroepithelial cells, and it increased apoptosis with the activation of caspase 3/8/9, PARP, and γH2AX. The phosphorylation of FGFR3 and its downstream targets were downregulated by SP-2. Meanwhile, it induced autophagy in BC cells as evidenced by LC3-II formation and p62 downregulation. The inhibition of autophagy using pharmacological inhibitors or through an ATG5-knockout protected RT-112 cells from SP-2-induced cell viability suppression and apoptosis. In addition, the upregulation of DAPK2 mRNA and protein expression also contributed to SP-2-induced cytotoxicity and apoptosis. In RT-112 cells, an FGFR3-TACC3-knockout caused the downregulation of DAPK2, autophagy, and apoptosis. In conclusion, this is the first study demonstrating that SP-2 exhibits potent anti-BC activity by suppressing the FGFR3-TACC3/Akt/mTOR pathway, which further activates a novel autophagy/DAPK2/apoptosis signaling cascade.