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The transcriptional activity of its product menin promotes the expression of genes deputed to several cellular mechanism including cell death. Here, we focused on its implication in the activation of the initiator and executioner caspases after staurosporine mediated cell death in 2D and 3D human and murine cell models. The administration of staurosporine, a well-known inducer of apoptotic cell death, caused a significant reduction of BON1, QGP1 and HPSC2.2 cell viability. The transient knockdown of <jats:italic>MEN1,<\/jats:italic> performed by using a specific siRNA, caused a significant down-regulation of <jats:italic>CDKN1A<\/jats:italic> and <jats:italic>TP53<\/jats:italic> transcripts. The treatment with 1\u00a0\u00b5M of staurosporine caused also a significant down-regulation of <jats:italic>MEN1<\/jats:italic> and was able to restore the basal expression of <jats:italic>TP53<\/jats:italic> only in QGP1 cells. Transient or permanent <jats:italic>MEN1<\/jats:italic> inactivation caused a decrease of caspase 8 activity in BON1, HPSC2.2 cells and <jats:italic>MEN1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> MEFs treated with staurosporine. Caspase 3\/7 activity was suppressed after administration of staurosporine in <jats:italic>MEN1<\/jats:italic> knocked down HPSC2.2 and <jats:italic>MEN1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> MEFs as well. The cleaved caspase 8 and caspase 3 decreased in human cells after <jats:italic>MEN1<\/jats:italic> knockdown and in <jats:italic>MEN1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> MEFs. The treatment with staurosporine caused a reduction of the size of <jats:italic>MEN1<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup> MEFs spheroids. Instead, <jats:italic>MEN1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> MEFs spheroids did not show any significant reduction of their size. In conclusion, <jats:italic>MEN1<\/jats:italic> controls the activity of the initiator caspase 8 and the executioner caspase 3 in human and murine cells. Restoring of a functional <jats:italic>MEN1<\/jats:italic> and interfering with the apoptotic mechanism could represent a future strategy for the treatment of <jats:italic>MEN1<\/jats:italic>-related malignancies.<\/jats:p>","DOI":"10.1007\/s10495-021-01700-1","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T10:06:31Z","timestamp":1638957991000},"page":"70-79","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells"],"prefix":"10.1007","volume":"27","author":[{"given":"Nele","family":"Wagener","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Buchholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Bertolino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang X.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0091-8498","authenticated-orcid":false,"given":"Pietro","family":"Di Fazio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"issue":"9","key":"1700_CR1","doi-asserted-by":"publisher","first-page":"2990","DOI":"10.1210\/jc.2012-1230","volume":"97","author":"RV Thakker","year":"2012","unstructured":"Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR et al (2012) Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). 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