Astaxanthin down-regulates Rad51 expression via inactivation of AKT kinase to enhance mitomycin C-induced cytotoxicity in human non-small cell lung cancer cells

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• 作者：Jen-Chung Ko^a ; ^b ; ¹ ; Jyh-Cheng Chen^c ; ¹ ; Tai-Jing Wang^d ; Hao-Yu Zheng^d ; Wen-Ching Chen^d ; Po-Yuan Chang^d ; Yun-Wei Lin^d ; ^{linyw@mail.ncyu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Astaxanthin (PubChem CID ; 5281224) ; Mitomycin C (PubChem CID ; 5746) ; Actinomycin D (PubChem CID ; 2019) ; Cycloheximide (PubChem CID ; 6197) ; MG132 (PubChem CID ; 462382) ; Leupeptin (PubChem CID ; 72429) ; LY294002 (PubChem CID ; 3973) ; Wortmannin (PubChem CID ; 312145) ; Trypan blue (PubChem CID ; 9562061) ; Sodium bicarbonate (PubChem CID ; 516892) ; l-Glutamine (PubChem CID ; 5961) ; Penicillin (PubChem CID ; 5904) ; Streptomycin (PubChem CID ; 19649) ; Crystal violet (PubChem CID ; 11057)
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 April 2016
• 年：2016
• 卷：105
• 期：Complete
• 页码：91-100
• 全文大小：2911 K

文摘

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.