Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway

Abstract

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1).

Targeting Inflammatory Signaling in Prostate Cancer Castration Resistance

“…Imipramine(10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanaminehydr ochloride), a member of the TCA family, attenuates PCa proliferation, migration, and invasion in PC-3 cells and xenograft mouse models. Imipramine inhibits IκBα phosphorylation and p65/RelA nuclear translocation, resulting in reduced secretion of some pro-inflammatory chemokines and cytokines, including TNFα and IL1β [83].…”

Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide

“…42 Studies have shown that imipramine exhibits inhibition role in several types of tumours although the specific mechanism remained unclear. 11,12,43 A recent study has demonstrated that TCAs induce hepatic stellate cell inactivation through increasing the sphingolipid ceramide, which was regard as a potent inhibitor of YAP signaling. 23 We proposed that important neurotransmitters and enzymes may be involved in the biological modulation process of imipramine on YAP in glioma directly or indirectly.…”

“… 42 Studies have shown that imipramine exhibits inhibition role in several types of tumours although the specific mechanism remained unclear. 11 , 12 , 43 A previous study by Shchors et al demonstrated that imipramine reduces cell viability and increased survival in glioma‐bearing mice by elevating cAMP levels, a modulator of autophagy. 44 Furthermore, Hsu et al reported that imipramine induces apoptosis through inhibiting NF‐κB signalling pathway.…”

“… 6 , 7 , 8 Imipramine, a tricyclic antidepressant (TCA) that functions by inhibiting serotonin and norepinephrine reuptake in the central nervous system (CNS), 9 , 10 is currently considered to possess anti‐tumour ability in various non‐CNS tumours, such as small cell lung cancer, prostate cancer, colorectal cancer and lymphomas. 11 , 12 , 13 However, there are few studies to explore the influence of imipramine on glioma and the results provided by previous studies were inconsistent and controversial. For example, Levkovitz et al reported that imipramine did not induce apoptosis, while Jeon et al found that imipramine enhanced autophagic and apoptotic activities of glioma cells.…”

Inhibition of Neutrophil Secretion Upon Adhesion as a Basis for the Anti-Inflammatory Effect of the Tricyclic Antidepressant Imipramine

“…The anti-invasive and anti-proliferative activity of imipramine has been demonstrated on various cancer cells such as small cell lung cancer, neuroendocrine pancreatic cancer, and prostate cancer cells (Jahchan et al, 2013;Barlaz Us et al, 2019). Imipramine (50-100 μM) attenuates cell migration and invasion of metastatic castration-resistant PC-3 prostate cancer cells or colorectalcancer cells (Alburquerque-González et al, 2020;Lim et al, 2020). Recently, imipramine blue, an organic derivative of the antidepressant drug imipramine, has been shown to effectively repress invasion of glioma or head and neck squamous carcinoma cells (Munson et al, 2012;Yang et al, 2016).…”