Long-Term Inhibition of Notch in A-375 Melanoma Cells Enhances Tumor Growth Through the Enhancement of AXIN1, CSNK2A3, and CEBPA2 as Intermediate Genes in Wnt and Notch Pathways
| Autor: | Mahsa Mohammadi, Masoumeh Azimi, Niloofar Sodeifi, Maryam Mehdipour, Marzieh Ebrahimi, Faezeh Keyghobadi, Abolfazl Kheimeh, Vahab Nekoukar, Javad Firouzi, Vajihe Azimian Zavareh, Fatemeh Nobakht Lahrood |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Notch signaling pathway Motility xenograft model lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine In vivo Cancer stem cell medicine melanoma HES1 Chemistry Melanoma Wnt signaling pathway medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Stem cell DAPT mathematical model |
| Zdroj: | Frontiers in Oncology, Vol 10 (2020) |
| Popis: | Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the short-term and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both in vitro and in vivo using xenograft models. In A375 with B-raf mutation, DAPT decreased the level of NOTCH1, NOTH2, and HES1 as downstream genes of the Notch pathway. This was accompanied by enhanced apoptosis after 24 h treatment, arrest in the G2-M phase, and impaired ability of colony and melanosphere formation at the short term. Moreover, tumor growth also reduced during 13 days of treatment. However, long-term treatment of DAPT promoted tumor growth in the xenograft model and enhanced the number and size of colonies and spheroids in vitro. The gene expression studies confirmed the up-regulation of Wnt and Notch downstream genes as well as AXIN1, CSNK2A3, and CEBPA2 following the removal of Notch inhibitor in vitro and in the xenograft model. Moreover, the Gompertz-based mathematical model determined a new drug resistance term in the present study. Our data supported that the long-term and not short-term inhibition of Notch by DAPT may enhance tumor growth and motility through up-regulation of AXIN1, CSNK2A3, and CEBPA2 genes in B-raf mutated A375 cells. |
| Databáze: | OpenAIRE |
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