Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells.
نویسندگان
چکیده
Myeloid-derived suppressor cells (MDSC) play an important role in tumor escape by suppressing T-cell responses. MDSC represent a group of cells of myeloid lineage at different stages of differentiation. Increased arginase activity and production of reactive oxygen species (ROS) are among the main functional characteristics of these cells. Recent studies have shown that all-trans retinoic acid (ATRA) had a potent activity in eliminating MDSC in cancer patients and in tumor-bearing mice. ATRA differentiates these cells into mature myeloid cells. However, the mechanism of this effect is unclear. Here, we have shown that ATRA dramatically and specifically up-regulated gene expression and protein level of glutathione synthase (GSS) in MDSC. This resulted in accumulation of glutathione (GSH) in these cells, observed in both mice and cancer patients. Blockade of GSH synthesis cancelled the effect of ATRA on MDSC. Accumulation of GSH in these cells using N-acetyl-L-cysteine mimicked the effect of ATRA on MDSC differentiation. Analysis of potential mechanisms of ATRA effect on GSS revealed that ATRA regulates its expression not by directly binding to the promoter but primarily via activation of extracellular signal-regulated kinase 1/2. Thus, ATRA induced differentiation of MDSC primarily via neutralization of high ROS production in these cells. This novel mechanism involves specific up-regulation of GSS and accumulation of GSH and could be used in developing and monitoring therapeutic application of ATRA.
منابع مشابه
تاثیر غلظت‌های مختلف ال- ترانس رتینوئیک اسید بر رشد و بقای سلول‌های بنیادی فولیکول موی موش سوری
Background and Objective: Hair follicle stem cells are multipotent, located in the bulge area, and are highly proliferating. Retinoids have an effect on epidermal differentiation and keratinization. Retinoic acid is used to treat some skin diseases such as Melasma, Acne and Ichthyosis. So, the study of all-trans retinoic acid effect on hair follicle stem cells and determination of the effective...
متن کاملMultiple Low Doses of 5-Fluorouracil Diminishes Immunosuppression by Myeloid Derived Suppressor Cells in Murine Melanoma Model
Background: Melanoma progression and metastasis is suggested to be mediated by increased accumulation of myeloid derived suppressor cells. Various chemotherapeutic drugs such as 5-Fluorouracil in single low concentration have the capacity, at least in part, to reverse tumor progression by reducing myeloid derived suppressor cellsmediated immunosuppression. Objective: To assess whether multiple ...
متن کاملافزایش اثرات درمانی سیس پلاتین و 5- فلورواوراسیل بر روی رده‌های سلولی AGS و KYSE-30 با استفاده از تیمار ترکیبی رتینوئیک اسید تمام ترانس
Backgrounds and Objectives: All-trans retinoic acid (ATRA) which is a derivative of vitamin A, exert fundamental effects on regulation of cell growth, differenation and apoptosis. Recently, resistance to cisplatin and 5-fluorouracil developed in gastric adenocarcinoma and squamous cell carcinoma. In this study, we investigated the combination treatment of ATRA with cisplatin and 5-fluorouracil ...
متن کاملAll-trans Retinoic Acid Regulates the Balance of Treg-Th17 Cells through ERK and P38 Signaling Pathway
متن کامل
Analysis of Promyelocytic Leukemia in Human Embryonic Carcinoma Stem Cells During Retinoic Acid-Induced Neural Differentiation
Background: Promyelocytic leukemia protein (PML) is a tumor suppressor protein that is involved in myeloid cell differentiation in response to retinoic acid (RA). In addition, RA acts as a natural morphogen in neural development. Objectives: This study aimed to examine PML gene expression in different stages of in vitro neural differentiation of NT2 cells, and to investigate the possible role o...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Cancer research
دوره 67 22 شماره
صفحات -
تاریخ انتشار 2007