Astaxanthin down-regulates Rad51 expression via inactivation of AKT kinase to enhance mitomycin C-induced cytotoxicity in human non-small cell lung cancer cells
Journal
Biochemical Pharmacology
Journal Volume
105
Pages
91-100
Date Issued
2016
Author(s)
Abstract
Astaxanthin has been demonstrated to exhibit a wide range of beneficial effects, including anti-inflammatory and anti-cancer properties. However, the molecular mechanism of astaxanthin-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Rad51 plays a central role in homologous recombination, and studies show that chemo-resistant carcinomas exhibit high levels of Rad51 expression. In this study, astaxanthin treatment inhibited cell viability and proliferation of two NSCLC cells, A549 and H1703. Astaxanthin treatment (2.5-20 μM) decreased Rad51 expression and phospho-AKT(Ser473) protein level in a time and dose-dependent manner. Furthermore, expression of constitutively active AKT (AKT-CA) vector rescued the decreased Rad51 mRNA and protein levels in astaxanthin-treated NSCLC cells. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitors (LY294002 or wortmannin) further decreased the Rad51 expression in astaxanthin-exposed A549 and H1703 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA or cotreatment with LY294002 further enhanced the cytotoxicity and cell growth inhibition of astaxanthin. Additionally, mitomycin C (MMC) as an anti-tumor antibiotic is widely used in clinical NSCLC chemotherapy. Combination of MMC and astaxanthin synergistically resulted in cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced phospho-AKT(Ser473) level and Rad51 expression. Overexpression of AKT-CA or Flag-tagged Rad51 reversed the astaxanthin and MMC-induced synergistic cytotoxicity. In contrast, pretreatment with LY294002 further decreased the cell viability in astaxanthin and MMC co-treated cells. In conclusion, astaxanthin enhances MMC-induced cytotoxicity by decreasing Rad51 expression and AKT activation. These findings may provide rationale to combine astaxanthin with MMC for the treatment of NSCLC. ? 2016 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
2 morpholino 8 phenylchromone; astaxanthin; messenger RNA; mitomycin; protein kinase B; Rad51 protein; wortmannin; antineoplastic antibiotic; astaxanthin; mitomycin; oncoprotein; Rad51 protein; RAD51 protein, human; xanthophyll; Article; cell growth; cell proliferation; cell viability; controlled study; down regulation; drug cytotoxicity; drug potentiation; enzyme inactivation; gene overexpression; growth inhibition; human; human cell; non small cell lung cancer; priority journal; protein expression; antagonists and inhibitors; biosynthesis; Carcinoma, Non-Small-Cell Lung; cell survival; dose response; down regulation; drug effects; Lung Neoplasms; metabolism; physiology; tumor cell line; Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Humans; Lung Neoplasms; Mitomycin; Oncogene Protein v-akt; Rad51 Recombinase; Xanthophylls
Publisher
Elsevier Inc.
Type
journal article