4.7 Article

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

Journal

MARINE DRUGS
Volume 21, Issue 2, Pages -

Publisher

MDPI
DOI: 10.3390/md21020073

Keywords

bladder cancer; stellettin B; apoptosis; autophagy; DAPK2

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Bladder cancer (BC) is a common and urgent medical issue, yet the current treatment approaches have limited effectiveness. This study investigated the anti-BC activity of SP-2, a triterpene isolated from a marine sponge. SP-2 suppressed BC cell viability and induced apoptosis through the inhibition of the FGFR3-TACC3/Akt/mTOR pathway, and it also triggered autophagy and upregulated DAPK2 expression to enhance cytotoxicity and apoptosis.
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 Rhabdastrella 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 gamma H2AX. 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.

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