Department of Urology, Show Chwan Memorial Hospital, Changhua, Taiwan, ROC; Division of Urology, Department of Surgery, Chang Bing Show-Chwan Memorial Hospital, Changhua, Taiwan, ROC.
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, ROC.
Biomed Pharmacother. 2023 Aug;164:114962. doi: 10.1016/j.biopha.2023.114962. Epub 2023 Jun 3.
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.
膀胱癌是全球十大最常见癌症类型之一，主要可分为肌层浸润性膀胱癌（MIBC）和非肌层浸润性膀胱癌（NMIBC）。然而，在包括根治性膀胱切除术或同步放化疗在内的标准治疗下，膀胱癌的预后仍然较差。大量研究报告称，膀胱癌的预后与信号转导和转录激活因子 3（STAT3）和核因子 kappa-B（NF-κB）的激活有关。氟西汀是一种众所周知的抗抑郁药，已被报道可对抗多种类型的癌症。然而，尚不清楚氟西汀是否通过靶向 STAT3 和 NF-κB 介导的信号通路来抑制膀胱癌的进展。在这里，我们使用细胞活力、凋亡测定、划痕愈合测定、侵袭/迁移测定、Western blot 测定、免疫荧光染色以及动物实验，阐明了氟西汀对体外和体内膀胱癌模型的疗效。我们发现氟西汀可能在膀胱癌中诱导细胞毒性和内在/外在细胞凋亡，并增强顺铂的潜力。氟西汀通过激活 caspase-3、8、9、凋亡诱导因子（AIF）和 EndG 来促进 caspase 依赖性和非依赖性凋亡信号。此外，氟西汀抑制侵袭和迁移能力以及转移相关基因的表达。还发现氟西汀可使 STAT3（Tyr705）和 NF-κB（Ser536）的磷酸化失活，并抑制 NF-κB 的核易位。在 MB49 荷瘤小鼠中，氟西汀有效地延迟了膀胱癌的进展，而没有引起一般毒性。总之，氟西汀诱导的细胞凋亡和抑制侵袭与 STAT3 和 NF-κB 的失活有关。
