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

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-cB). Fluoxetine, a well-known antidepressant, 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-cB-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-cB (Ser536) and suppress the nuclear translocation of NF-cB. 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-cB.

Automated summary

Bladder cancer, a common cancer type with poor prognosis, can be divided into MIBC and NMIBC. In this study, the efficacy of fluoxetine, an antidepressant, on BC was investigated. The results showed that fluoxetine induced cytotoxicity, apoptosis, and inhibited invasion and migration in BC cells. Fluoxetine also inactivated the phosphorylation of STAT3 and NF-cB and suppressed their nuclear translocation. In MB49-bearing mice, fluoxetine effectively delayed the progression of BC without inducing toxicity. Overall, fluoxetine targets STAT3 and NF-cB-mediated signaling to inhibit BC progression.