Background: Several researches have been performed with the aim of identifying drugs able in blocking PI3K/Akt pathway. We have already demonstrated that myo-Inositol (myo-Ins) treatment can block EMT in breast cancer cells by downregulating PI3K/Akt and inducing changes in cytoskeletal architecture. Aim: Herein, we set our experiments to investigate migration/invasiveness inhibition though in vitro and in vivo models upon myo-Ins administration. Methods: In vitro experiments were performed using both mesenchymal-like (MDA-MB-231) and epithelial-like (MCF-7) invasive human breast cancer cells. We used transwell assays for in vitro and Zebrafish embryos as in vivo models to evaluate migration and invasiveness. The expression of key genes involved in the mechanism was evaluated by qPCR, while gain- and loss-of-function approaches allowed identifying the specific dynamical relationships. Results: Myo-Ins inhibits motility and invasiveness only in MDA-MB-231 cells both in vitro and in vivo. In MDA cells, miR-125a-5p upregulation was linked to IP6K1 downregulation triggered by myo-Ins treatment. Silencing and overexpression experiments confirmed the key role of miR-125a-5p/IP6K1 axis in blocking cell motility. This effect was demonstrated to be myo-Ins-dependent MDM2 inhibition. Given that MDM2 in MCF-7 cells was unaffected by treatment, in these cells myo-Ins was unable in antagonizing motility. Conversely, both miR-125a-5p and IP6K1 were not modulated. However, MDM2 silencing restore sensitivity to myo-Ins, thus leading to a significant inhibition of the MCF-7 cells motility capability. Conclusions: Our results suggest that myo-Ins can inhibit motility in triple negative breast cancer. Such an effect is likely mediated by MDM2 inhibition, which, in turn, triggers a complex tumor reversion promoted by the miR-125a-5p/IP6K1 axis modulation. Elucidation of the role of miR-125a- 5p/IP6K1 axis will reveal strategies for molecular targeted therapies in breast cancer.
Myo-Inositol treatment inhibits motility in triple negative breast cancer via miR-125a-5p/IP6K1 axis / Minini, Mirko; Proietti, Sara; He, Xingkang; Senni, Alice; Monti, Noemi; Fuso, Andrea; Cucina, Alessandra; Cao, Yihai; Bizzarri, Mariano. - (2019). (Intervento presentato al convegno EMBL CONFERENCE: Cancer Genomics tenutosi a EMBL Heidelberg, Germany).
Myo-Inositol treatment inhibits motility in triple negative breast cancer via miR-125a-5p/IP6K1 axis
Minini Mirko;Proietti Sara;Senni Alice;Monti Noemi;Fuso Andrea;Cucina Alessandra;Bizzarri Mariano
2019
Abstract
Background: Several researches have been performed with the aim of identifying drugs able in blocking PI3K/Akt pathway. We have already demonstrated that myo-Inositol (myo-Ins) treatment can block EMT in breast cancer cells by downregulating PI3K/Akt and inducing changes in cytoskeletal architecture. Aim: Herein, we set our experiments to investigate migration/invasiveness inhibition though in vitro and in vivo models upon myo-Ins administration. Methods: In vitro experiments were performed using both mesenchymal-like (MDA-MB-231) and epithelial-like (MCF-7) invasive human breast cancer cells. We used transwell assays for in vitro and Zebrafish embryos as in vivo models to evaluate migration and invasiveness. The expression of key genes involved in the mechanism was evaluated by qPCR, while gain- and loss-of-function approaches allowed identifying the specific dynamical relationships. Results: Myo-Ins inhibits motility and invasiveness only in MDA-MB-231 cells both in vitro and in vivo. In MDA cells, miR-125a-5p upregulation was linked to IP6K1 downregulation triggered by myo-Ins treatment. Silencing and overexpression experiments confirmed the key role of miR-125a-5p/IP6K1 axis in blocking cell motility. This effect was demonstrated to be myo-Ins-dependent MDM2 inhibition. Given that MDM2 in MCF-7 cells was unaffected by treatment, in these cells myo-Ins was unable in antagonizing motility. Conversely, both miR-125a-5p and IP6K1 were not modulated. However, MDM2 silencing restore sensitivity to myo-Ins, thus leading to a significant inhibition of the MCF-7 cells motility capability. Conclusions: Our results suggest that myo-Ins can inhibit motility in triple negative breast cancer. Such an effect is likely mediated by MDM2 inhibition, which, in turn, triggers a complex tumor reversion promoted by the miR-125a-5p/IP6K1 axis modulation. Elucidation of the role of miR-125a- 5p/IP6K1 axis will reveal strategies for molecular targeted therapies in breast cancer.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
