Disruption of oncogenic pathways in mucoepidermoid carcinoma: CREB inhibitor 666.15 as a potential therapeutic agent

IF 4 2区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Oral oncology Pub Date : 2024-09-26 DOI:10.1016/j.oraloncology.2024.107029

Maria Eduarda Pérez-de-Oliveira , Vivian Petersen Wagner , Colin D. Bingle , Pablo Agustin Vargas , Lynne Bingle

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Abstract

Objectives: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumour with around 50 % of cases carrying the CRTC1-MAML2 translocation. The CREB pathway has been associated with the transforming activity of this translocation. The aim of this study was to determine the effects of CREB inhibition on MEC cell behaviour in vitro. Material and Methods: Two translocation-positive (UM-HMC-2 and H292) and one translocation-negative (H253) MEC cell lines were treated with 666.15, a CREB inhibitor. Drug IC50 doses were determined for each cell line. Clonogenic and spheroid assays were used to assess survival, including percentage of cancer stem cells, and transwell and scratch assays evaluated invasive and migratory capacities, respectively. Immunofluorescence staining was used to determine E-cadherin expression. Results: CREB inhibition significantly reduced the number of surviving colonies and spheroids and delayed cell invasion in all cell lines, but this was more significant in the fusion positive, UM-HMC-2 cells. The expression of E-cadherin was significantly higher in treated UM-HMC-2 and H292 cells. Conclusion: CREB inhibition with 666.15 impaired key MEC oncogenic behaviours associated with metastasis and drug resistance, including cell invasion and survival.

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粘液表皮样癌致癌途径的中断：CREB 抑制剂 666.15 作为一种潜在的治疗药物

研究目的蕈样表皮样癌（MEC）是最常见的恶性唾液腺肿瘤，约 50% 的病例携带 CRTC1-MAML2 易位。CREB通路与这种易位的转化活性有关。本研究旨在确定 CREB 抑制对 MEC 细胞体外行为的影响。材料与方法：用 CREB 抑制剂 666.15 处理两种易位阳性（UM-HMC-2 和 H292）和一种易位阴性（H253）的 MEC 细胞系。确定了每种细胞系的药物 IC50 剂量。克隆形成试验和球形试验用于评估存活率，包括癌症干细胞的百分比，而透孔试验和划痕试验则分别评估侵袭能力和迁移能力。免疫荧光染色用于确定 E-cadherin的表达。结果在所有细胞系中，CREB抑制都能明显减少存活菌落和球形细胞的数量，延缓细胞侵袭，但这在融合阳性的UM-HMC-2细胞中更为明显。经处理的 UM-HMC-2 和 H292 细胞中 E-cadherin 的表达明显升高。结论用 666.15 抑制 CREB 会损害与转移和耐药性相关的 MEC 关键致癌行为，包括细胞侵袭和存活。

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来源期刊

Oral oncology 医学-牙科与口腔外科

CiteScore

8.70

自引率

10.40%

发文量

505

审稿时长

20 days

期刊介绍： Oral Oncology is an international interdisciplinary journal which publishes high quality original research, clinical trials and review articles, editorials, and commentaries relating to the etiopathogenesis, epidemiology, prevention, clinical features, diagnosis, treatment and management of patients with neoplasms in the head and neck. Oral Oncology is of interest to head and neck surgeons, radiation and medical oncologists, maxillo-facial surgeons, oto-rhino-laryngologists, plastic surgeons, pathologists, scientists, oral medical specialists, special care dentists, dental care professionals, general dental practitioners, public health physicians, palliative care physicians, nurses, radiologists, radiographers, dieticians, occupational therapists, speech and language therapists, nutritionists, clinical and health psychologists and counselors, professionals in end of life care, as well as others interested in these fields.