The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells.
نویسندگان
چکیده
Disruption of the apoptotic pathways may account for resistance to chemotherapy and treatment failures in human neoplastic disease. To further evaluate this issue, we isolated a HL-60 cell clone highly resistant to several drugs inducing apoptosis and to the differentiating chemical all-trans-retinoic acid (ATRA). The resistant clone displayed an activated phosphoinositide 3-kinase (PI3K)/AKT1 pathway, with levels of phosphatidylinositol (3,4,5) trisphosphate higher than the parental cells and increased levels of both Thr 308 and Ser 473 phosphorylated AKT1. In vitro AKT1 activity was elevated in resistant cells, whereas treatment of the resistant cell clone with two inhibitors of PI3K, wortmannin or Ly294002, strongly reduced phosphatidylinositol (3,4,5) trisphosphate levels and AKT1 activity. The inhibitors reversed resistance to drugs. Resistant cells overexpressing either dominant negative PI3K or dominant negative AKT1 became sensitive to drugs and ATRA. Conversely, if parental HL-60 cells were forced to overexpress an activated AKT1, they became resistant to apoptotic inducers and ATRA. There was a tight relationship between the activation of the PI3K/AKT1 axis and the expression of c-IAP1 and c-IAP2 proteins. Activation of the PI3K/AKT1 axis in resistant cells was dependent on enhanced tyrosine phosphorylation of the p85 regulatory subunit of PI3K, conceivably due to an autocrine insulin-like growth factor-I production. Our findings suggest that an up-regulation of the PI3K/AKT1 pathway might be one of the survival mechanisms responsible for the onset of resistance to chemotherapeutic and differentiating therapy in patients with acute leukemia.
منابع مشابه
All-trans Retinoic Acid Regulates the Balance of Treg-Th17 Cells through ERK and P38 Signaling Pathway
متن کامل
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 کاملGelatin Microspheres for the Controlled Release of All-trans-Retinoic Acid Topical Formulation and Drug Delivery Evaluation
A topical o/w cream containing tretinoin microspheres was prepared. Gelatin microspheres of tretinoin were prepared using coacervation method. These microspheres contained about 50% w/w tretinoin. The particle size range of microspheres was between 90-150 m m. In vitro drug release from microspheres and a cream formulation was studied. It was shown that drug release from microspheres followed H...
متن کاملGelatin Microspheres for the Controlled Release of All-trans-Retinoic Acid Topical Formulation and Drug Delivery Evaluation
A topical o/w cream containing tretinoin microspheres was prepared. Gelatin microspheres of tretinoin were prepared using coacervation method. These microspheres contained about 50% w/w tretinoin. The particle size range of microspheres was between 90-150 m m. In vitro drug release from microspheres and a cream formulation was studied. It was shown that drug release from microspheres followed H...
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 کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Molecular cancer research : MCR
دوره 1 3 شماره
صفحات -
تاریخ انتشار 2003