Adenovirus E2F1 overexpression sensitizes LNCaP and PC3 prostate tumor cells to radiation in vivo.
Adenovirus E2F1 overexpression sensitizes LNCaP and PC3 prostate tumor cells to radiation in vivo.
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DOI：
10.1016/j.ijrobp.2010.08.013
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发表时间：
2011-02-01
影响因子：
7
通讯作者：
Pollack, Alan
中科院分区：
文献类型：
--
作者：
Udayakumar, Thirupandiyur S.;Stoyanova, Radka;Hachem, Paul;Ahmed, Mansoor M.;Pollack, Alan
我们之前在体外证明过表达E2F1使前列腺癌细胞放射增敏。在这里，我们证明了Ad-E2F1对生长LNCaP（原位）和PC3（皮下）裸鼠异种移植肿瘤的放射增敏效果。在接受或不接受放射治疗的LNCaP （3×108 PFU）和PC3 （5×108 PFU）肿瘤中瘤内注射腺病毒E2F1。LNCaP肿瘤采用MRI检测肿瘤体积（TV）， PC3肿瘤采用卡钳检测，LNCaP肿瘤采用ELISA检测血清PSA水平。TUNEL染色检测细胞凋亡，Western blot分析细胞死亡信号通路的关键蛋白。与腺病毒荧光素酶（Ad-Luc）对照相比，细胞内过表达Ad-E2F1对TV的消退和PSA的降低有显著作用。与Ad-Luc对照（PSA-59 ng/ml/TV-218 mm3, p<0.05）相比，Ad-E2F1对LNCaP肿瘤生长的体内抑制作用显著（PSA-34 ng/ml/TV-142 mm3）。放射治疗显著增强了这种作用（与Ad-Luc/PSA-42 ng/ml/TV-174 mm3相比，PSA-16 ng/ml/TV-55 mm3; p<0.05）。对于PC3肿瘤，Ad-E2F1单独使用效果最大，RT联合使用效果很小或没有效果。然而，RT的加入提高了PC3肿瘤的原位凋亡水平。从分子上讲，Ad-E2F1在联合作用下消除了辐射诱导的BCL-2蛋白，并与活化的BAX增加相关，无论p53和AR功能状态如何，共同引起了强有力的放射增敏效应。我们首次在体内用腺病毒载体异位过表达E2F1显著抑制裸小鼠原位p53野生型LNCaP和皮下p53null PC3肿瘤。此外，我们还证实了E2F1能使LNCaP肿瘤对rt强致敏。这些发现表明，E2F1过表达能使前列腺肿瘤细胞在体内不依赖于p53或雄激素受体状态而致敏。
We previously showed that E2F1 overexpression radiosensitizes prostate cancer cells in-vitro. Here, we demonstrate the radiosensitization efficacy of Ad-E2F1 in growing LNCaP (orthotopically) and PC3 (subcutaneously) nude mice xenograft tumors. Adenoviral E2F1 was injected intra-tumorally in LNCaP (3×108 PFU) and PC3 (5×108 PFU) tumors treated with or without radiation. Tumor volumes (TV) were measured by MRI in LNCaP tumors, calipers in PC3 tumors and serum PSA levels by ELISA in LNCaP tumors. Apoptosis was measured by TUNEL staining and key proteins involved in cell death signaling were analyzed by Western blot. Intracellular overexpression of Ad-E2F1 had significant effect in the regression of TV and reducing the PSA relative to adenoviral luciferase (Ad-Luc) control. The in-vivo regressing effect of Ad-E2F1 on LNCaP tumor growth was significant (PSA-34 ng/ml/TV-142 mm3) compared to Ad-Luc control (PSA-59 ng/ml/TV-218 mm3; p<0.05). This effect was significantly enhanced by radiation therapy (PSA-16 ng/ml/TV-55 mm3 compared to Ad-Luc/PSA-42 ng/ml/TV-174 mm3; p<0.05). For PC3 tumors, the greatest effect was observed with Ad-E2F1 alone, there was little or no effect when RT was combined. However, addition of RT enhanced the level of in-situ apoptosis in PC3 tumors. Molecularly, Ad-E2F1 in a combination setting abrogated radiation induced BCL-2 protein and was associated with an increase in activated BAX, together caused a potent radiosensitizing effect irrespective of p53 and AR functional status. We show here for the first time that ectopic overexpression of E2F1 in-vivo using an adenoviral vector significantly inhibits orthotopic p53wild-type LNCaP and subcutaneous p53null PC3 tumors in nude mice. Furthermore, we demonstrate that E2F1 strongly sensitizes LNCaP tumors to RT. These findings suggest that E2F1 overexpression can sensitize prostate tumor cells in-vivo independent of p53 or androgen receptor status.
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影响因子：
24.3
作者：
Kuhn, H;Liebers, U;Wolff, G
通讯作者：
Wolff, G
DOI：
10.1016/j.ijrobp.2005.04.033
发表时间：
2005-09-01
影响因子：
7
作者：
Nguyen, KH;Hachem, P;Pollack, A
通讯作者：
Pollack, A
影响因子：
5.3
作者：
Nip, J;Strom, DK;Hiebert, SW
通讯作者：
Hiebert, SW
影响因子：
64.8
作者：
Morris, Erick J.;Ji, Jun-Yuan;Yang, Fajun;Di Stefano, Luisa;Herr, Anabel;Moon, Nam-Sung;Kwon, Eun-Jeong;Haigis, Kevin M.;Naar, Anders M.;Dyson, Nicholas J.
通讯作者：
Dyson, Nicholas J.
影响因子：
8
作者：
Croxton, R;Ma, YH;Cress, WD
通讯作者：
Cress, WD