EPS8 inhibition increases cisplatin sensitivity in lung cancer cells.
EPS8 inhibition increases cisplatin sensitivity in lung cancer cells.
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DOI：
10.1371/journal.pone.0082220
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dolan ME
中科院分区：
文献类型：
--
作者：
Gorsic LK;Stark AL;Wheeler HE;Wong SS;Im HK;Dolan ME
Cisplatin, a commonly used chemotherapeutic, is associated with ototoxicity, renal toxicity and neurotoxicity, thus identifying means to increase the therapeutic index of cisplatin may allow for improved outcomes. A SNP (rs4343077) within EPS8, discovered through a genome wide association study of cisplatin-induced cytotoxicity and apoptosis in lymphoblastoid cell lines (LCLs), provided impetus to further study this gene. The purpose of this work was to evaluate the role of EPS8 in cellular susceptibility to cisplatin in cancerous and non-cancerous cells. We used EPS8 RNA interference to determine the effect of decreased EPS8 expression on LCL and A549 lung cancer cell sensitivity to cisplatin. EPS8 knockdown in LCLs resulted in a 7.9% increase in cisplatin-induced survival (P = 1.98×10−7) and an 8.7% decrease in apoptosis (P = 0.004) compared to control. In contrast, reduced EPS8 expression in lung cancer cells resulted in a 20.6% decrease in cisplatin-induced survival (P = 5.08×10−5). We then investigated an EPS8 inhibitor, mithramycin A, as a potential agent to increase the therapeutic index of cisplatin. Mithramycin A decreased EPS8 expression in LCLs resulting in decreased cellular sensitivity to cisplatin as evidenced by lower caspase 3/7 activation following cisplatin treatment (42.7%±6.8% relative to control P = 0.0002). In 5 non-small-cell lung carcinoma (NSCLC) cell lines, mithramycin A also resulted in decreased EPS8 expression. Adding mithramycin to 4 NSCLC cell lines and a bladder cancer cell line, resulted in increased sensitivity to cisplatin that was significantly more pronounced in tumor cell lines than in LCL lines (p<0.0001). An EGFR mutant NSCLC cell line (H1975) showed no significant change in sensitivity to cisplatin with the addition of mithramycin treatment. Therefore, an inhibitor of EPS8, such as mithramycin A, could improve cisplatin treatment by increasing sensitivity of tumor relative to normal cells.
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影响因子：
14.9
作者：
Barceló F;Scotta C;Ortiz-Lombardía M;Méndez C;Salas JA;Portugal J
通讯作者：
Portugal J
DOI：
10.1158/1078-0432.ccr-11-0724
发表时间：
2011-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Huang RS;Johnatty SE;Gamazon ER;Im HK;Ziliak D;Duan S;Zhang W;Kistner EO;Chen P;Beesley J;Mi S;O'Donnell PH;Fraiman YS;Das S;Cox NJ;Lu Y;Macgregor S;Goode EL;Vierkant RA;Fridley BL;Hogdall E;Kjaer SK;Jensen A;Moysich KB;Grasela M;Odunsi K;Brown R;Paul J;Lambrechts D;Despierre E;Vergote I;Gross J;Karlan BY;Defazio A;Chenevix-Trench G;Australian Ovarian Cancer Study Group;Dolan ME
通讯作者：
Dolan ME
影响因子：
3.6
作者：
Petrovic V;Costa RH;Lau LF;Raychaudhuri P;Tyner AL
通讯作者：
Tyner AL
DOI：
10.2106/00004623-197254080-00013
发表时间：
1972-01-01
影响因子：
5.3
作者：
ELIAS, EG;EVANS, JT
通讯作者：
EVANS, JT
影响因子：
8
作者：
Liu, P-S;Jong, T-H;Leu, T-H
通讯作者：
Leu, T-H