Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor‐mediated transcription

Abstract

The purpose of this study was to examine the effect of tricyclic antidepressant desipramine (DMI) on the growth inhibition and translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus in cancerous and noncancerous cell lines and the effect of DMI on GR-mediated transcription. Nontumorigenic, immortalized keratinocytes cell line (3PC), papilloma (MT1/2), and squamous cell carcinoma (Ca3/7) cell lines were initially used to study the cell growth inhibition by DMI. Although, the growth of all three cell lines was suppressed by DMI, it was more effective in Ca3/7 cells. Therefore, we next examined the effect of DMI on Ca3/7 cells, resistant to growth inhibition by the synthetic glucocorticoid fluocinolone acetonide (FA). DMI inhibited cell proliferation in a time-dependent manner. The translocation of GR was induced by FA alone, DMI alone, and combination of both agents. FA induced GR-mediated transcription in Ca3/7 cells transfected with a luciferase reporter gene under the control of glucocorticoid response element (GRE), but DMI alone did not affect GR-mediated transcription. However, DMI inhibited FA-induced, GR-mediated transcription when both agents were given together. Pretreatment with DMI followed by combination of DMI and FA decreased GR-mediated transcription more than pretreatment with FA. The expression of metallothionein-1 (Mt-1) gene, which is regulated by GR, was induced significantly by the combination of DMI and FA, and enhanced significantly by pretreatment with FA but not DMI. DMI is suggested to inhibit the growth of Ca3/7 cells and to affect GR-mediated transcription.

Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells

“…1B). These results revealed that DMI obviously caused apoptotic damage to Ca3/7 cells, resulting in a decrease in cell viability as previously described (25).…”

“…The Ca3/7 cell line was obtained from squamous cell carcinomas induced in SENCAR mice by the standard two-stage DMBA/TPA protocol as previously described (25). Ca3/7 cells were cultured in Eagle's minimal essential medium with 0.05 mM of Ca 2+ supplemented with 4% charcoal-extracted, heat-inactivated fetal bovine serum, insulin (5 μg/ml), epidermal growth factor (5 ng/ml), transferrin (10 μg/ml) O-phosphoethanolamine (10 μM), ethanolamine (10 μM), glutamine (2 μM), penicillin (50 U/ml) and streptomycin (50 ng/ml).…”

“…In our previous study, we also examined the effect of DMI on the growth of three murine skin cell lines (3PC, MT1/2 and Ca3/7) representing different stages of skin carcinogenesis. All of the cell lines were treated with various concentrations of DMI for 12, 24, 48, 72, and 96 h which resulted in the suppression of cell growth in a dose-and time-dependent manner (25). In the present study we focused on the carcinomaproducing cell line Ca3/7 treated with 1, 10 or 20 μM DMI.…”

“…It was shown that MT1/2 and Ca3/7 cells were resistant to glucocorticoids due to an alteration of GR function, but not due to a reduction in GR expression or gene mutation. In our previous study (25), the ATP-bioluminescence assay was used to estimate the cell viability of the three murine keratinocyte cell lines, nontumorigenic 3PC, papilloma-derived MT1/2 and squamous cell carcinoma-derived Ca3/7, treated with DMI. We hypothesized that DMI causes a growth inhibitory effect, particularly on Ca3/7 cells by inducing GR translocation from the cytoplasm to the nucleus.…”

Antidepressants in association with reducing risk of oral cancer occurrence: a nationwide population-based cohort and nested case-control studies

“…Additionally, approximately 90% of oral cancers are squamous cell carcinoma. Kinjo et al also demonstrated SSRIs have antiproliferative effect in squamous carcinoma [ 31 ]. We believe that SSRIs could retard the growth of developed tumors by inhibiting tumor cell proliferation [ 32 ].…”