Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth.
Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth.
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同源重组（HR）是一种在正常细胞中准确修复DNA的机制，在癌症中失调。升高/失调的HR与基因组不稳定性和端粒维持有关，这是癌细胞的关键生命线。我们先前已经表明，HR活性升高，并显着有助于BAC中的基因组不稳定性。本研究的目的是评估HR抑制单独和与端粒酶抑制组合在BAC中的治疗潜力。我们证明，端粒酶抑制BAC细胞增加HR活性，RAD 51的表达，并协会RAD 51端粒。随着时间的推移，HR的抑制导致BAC细胞中端粒缩短以及基因组不稳定性显著降低。HR抑制（无论是转基因的还是化学的）与端粒酶抑制的组合，相对于单独的任一种处理，在所有测试的BAC细胞系中引起端粒磨损和凋亡性死亡的显著增加。经处理的细胞的子集也对β-半乳糖苷酶染色呈阳性，表明衰老。联合治疗还与S期下降和强烈的G2/M停滞相关，表明大量端粒磨损。在皮下肿瘤模型中，联合治疗产生最小的肿瘤，甚至比单独治疗产生的肿瘤更小（P=0.001）。即使是从这些小鼠身上切除的肿瘤，端粒也明显减少，并有凋亡的迹象。因此，我们得出结论，虽然端粒被端粒酶延长，RAD 51/HR升高有助于它们在BAC细胞中的维持/稳定。端粒酶抑制剂阻止端粒延长，但诱导RAD 51/HR，这有助于端粒维持/稳定和防止细胞凋亡，降低治疗效果。将HR抑制与端粒酶组合，使端粒更容易降解并显著增加/加速其磨损，导致细胞凋亡。因此，我们证明了靶向HR和端粒酶的疗法具有防止BAC中的肿瘤生长和基因组进化的潜力。
Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in BAC. The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells increases HR activity, RAD51 expression, and association of RAD51 to telomeres. Suppression of HR leads to shorter telomeres as well as markedly reduced genomic instability in BAC cells over time. Combination of HR suppression (whether transgenic or chemical) with telomerase inhibition, causes a significant increase in telomere attrition and apoptotic death in all BAC cell lines tested, relative to either treatment alone. A subset of treated cells also stain positive for β-galactosidase, indicating senescence. The combined treatment is also associated with decline in S-phase and a strong G2/M arrest, indicating massive telomere attrition. In a subcutaneous tumor model, the combined treatment resulted in the smallest tumors, which were even smaller (P=0.001) than those resulted from either treatment alone. Even the tumors removed from these mice had significantly reduced telomeres and evidence of apoptosis. We therefore conclude that although telomeres are elongated by telomerase, elevated RAD51/HR assist in their maintenance/stabilization in BAC cells. Telomerase inhibitor prevents telomere elongation but induces RAD51/HR, which contribute to telomere maintenance/stabilization and prevention of apoptosis, reducing the efficacy of treatment. Combining HR inhibition with telomerase, makes telomeres more vulnerable to degradation and significantly increases/expedites their attrition, leading to apoptosis. We therefore demonstrate that a therapy, targeting HR and telomerase, has potential to prevent both the tumor growth and genomic evolution in BAC.
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影响因子：
16.8
作者：
通讯作者：
--
DOI：
10.1016/0921-8734(91)90018-7
发表时间：
1991-03-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
HARLEY, CB
通讯作者：
HARLEY, CB
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
8
作者：
Ducray, C;Pommier, JP;Sabatier, L
通讯作者：
Sabatier, L
影响因子：
11.4
作者：
BRYAN, TM;ENGLEZOU, A;REDDEL, RR
通讯作者：
REDDEL, RR