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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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 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.

Details

Title
Stellettin B Induces Cell Death in Bladder Cancer Via Activating the Autophagy/DAPK2/Apoptosis Signaling Cascade
Author
Chun-Han, Chang 1 ; Lin, Bo-Jyun 2 ; Chun-Han, Chen 2   VIAFID ORCID Logo  ; Nguyen, Nham-Linh 3 ; Tsung-Han Hsieh 4   VIAFID ORCID Logo  ; Jui-Hsin Su 5 ; Chen, Mei-Chuan 6 

 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan 
 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan 
 Faculty of Chemical and Food Technology, HCMC University of Technology and Education, Ho Chi Minh 70000, Vietnam 
 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 110, Taiwan 
 Department of Science Education, National Museum of Marine Biology and Aquarium, Pingtung 944401, Taiwan 
 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan; Traditional Herbal Medicine Research, Center of Taipei Medical University Hospital, Taipei 110, Taiwan; Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan 
First page
73
Publication year
2023
Publication date
2023
Publisher
MDPI AG
e-ISSN
16603397
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2779495097
Copyright
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.