Fluoxetine inactivates STAT3/NF-κB signaling and promotes sensitivity to cisplatin in bladder cancer

• Published in: Biomedicine & pharmacotherapy Vol. 164; p. 114962
• Main Authors: Yang, Che-Jui, Tan, Zhao-Lin, Yang, Jr-Di, Hsu, Fei-Ting, Chiang, Chih-Hung
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.08.2023; Elsevier
• Subjects: Animals; Apoptosis; Caspases - metabolism; Cell Line, Tumor; Cisplatin - metabolism; Cisplatin - pharmacology; Fluoxetine; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Mice; Muscles invasive bladder cancer; NF-kappa B - metabolism; NF-κB; STAT3; STAT3 Transcription Factor - metabolism; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; NF-κB; Fluoxetine; Muscles invasive bladder cancer; STAT3; Apoptosis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114962

Bladder cancer is known as one of the top ten most common cancer types worldwide and can be majorly divided into muscles invasive bladder cancer (MIBC) and non-muscles invasive type (NMIBC). However, the prognosis of BC remains poor under standard treatment including radical cystectomy or concurrent chemoradiotherapy. Numerous studies have reported that the prognosis of BC is associated with the activation of signal transducer and activator of transcription (STAT3) and nuclear factor kappa-B (NF-κB). Fluoxetine, a well-known anti-depressant, has been reported to against various type of cancers. However, it is unclear whether fluoxetine has the capacity to inhibit BC progression by targeting STAT3 and NF-κB-mediated signaling. Here, we used cell viability, apoptosis assay, wound healing assay, invasion/migration assay, Western blotting assay, immunofluorescence staining, as well as animal experiments, to elucidate the efficacy of fluoxetine on in vitro and in vivo BC models. We found that fluoxetine may induce cytotoxicity and intrinsic/extrinsic apoptosis in BC and enhance the potential of cisplatin. Fluoxetine promoted both caspase-dependent and caspase-independent apoptosis signaling by activating caspase-3, 8, 9, apoptosis-inducing factor (AIF), and EndG. Furthermore, fluoxetine suppressed invasion and migration ability and the expression of metastasis-associated genes. Fluoxetine was also found to inactivate the phosphorylation of STAT3 (Tyr705) and NF-κB (Ser536) and suppress the nuclear translocation of NF-κB. In MB49-bearing mice, fluoxetine effectively delayed the progression of BC without inducing general toxicity. In summary, the induction of apoptosis and the inhibition of invasion triggered by fluoxetine are associated with the inactivation of STAT3 and NF-κB. [Display omitted]