Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics
Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics
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DOI：
10.3892/ijo_00000580
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发表时间：
2010-04-01
影响因子：
5.2
通讯作者：
Popescu, Nicholas C.
中科院分区：
文献类型：
--
作者：
Zhou, Xiaoling;Yang, Xu-Yu;Popescu, Nicholas C.
肿瘤抑制基因的失活是癌症发生或发展的主要原因。人类肿瘤抑制基因DLC 1（在肝癌1中缺失）在多种癌症中经常下调或沉默，主要是通过表观遗传机制。随着表观遗传学治疗研究的不断深入和发展，许多有前途的抗肿瘤药物，特别是组蛋白去乙酰化酶（HDAC）抑制剂，已被开发并成功应用于临床。DLC 1和HDAC抑制剂均发挥抗肿瘤作用，它们的联合作用可用于更有效的癌症治疗。为了评估这种方法的潜在益处，我们研究了腺病毒（Ad）-DLC 1介导的转导和暴露于辛二酰苯胺异羟肟酸（SAHA）（一种强大的HDAC抑制剂）在两种缺乏固有DLC 1表达的人癌细胞系22 Rv 1前列腺癌细胞和7703 K人肝细胞癌细胞中的抑制作用。与DLC 1在几种癌症中的肿瘤抑制功能一致。包括前列腺癌和肝癌。Ad-DLC 1基因转染22 Rv 1和7703 K细胞后，细胞形态发生改变，诱导细胞凋亡，抑制细胞增殖、迁移和非贴壁生长。低浓度的SAHA（51 N）有效地恢复了22 Rv 1细胞中DLC 1的表达，所述22 Rv 1细胞由于历史脱乙酰化而缺乏DLC 1表达，但在7703 K细胞中具有最小的影响，其中DLC 1基因的沉默主要是由于启动子超甲基化。无论DLC 1失活的表观遗传机制如何，DLC 1转导细胞的SAHA处理对两种细胞系中的肿瘤、细胞增殖和肿瘤发生具有协同抑制作用。在22 Rv 1细胞中，这种组合方案几乎消除了半固体培养基中集落的形成，作为体外致瘤性的量度。目前的体外结果验证了该方案作为某些癌症的潜在新治疗选择。
Inactivation of tumor suppressor genes is a major contributing alteration in the initiation or progression of cancer. The human tumor suppressor gene DLC1 (deleted in liver cancer 1) is frequently downregulated or silenced in multiple cancers, predominantly by epigenetic mechanisms. With the Current considerable interest and progress in epigenetic therapy, a number of promising antineoplastic agents, particularly histone deacetylase (HDAC) inhibitors, have been developed and Used Successfully in clinical trials. Both DLC1 and HDAC inhibitors exert antineoplastic functions, and their combined action Could be exploited for a more effective cancer therapy. To evaluate the potential benefits of this approach, we examined the antineoplastic effects of adenoviral (Ad)-DLC1-mediated transduction and exposure to suberoylanilide hydroxamic acid (SAHA), a powerful HDAC inhibitor, in two human cancer cell lines that lack intrinsic DLC1 expression, 22Rv1 prostate cancer cells and 7703K human hepatocellular carcinoma cells. Consistent with the oncosuppressive function of DLC1 in several cancers. including prostate and liver cancer. transduction of 22Rv1 and 7703K cells with all Ad-DLC1 expression vector resulted in alterations of cell morphology, induction of apoptosis, and inhibition of cell proliferation, migration, and anchorage-independent growth. A low concentration of SAHA (5 IN) efficiently restored the expression of DLC1 in 22Rv1 cells that lack DLC1 expression due to historic deacetylation but had a minimal effect in 7703K cells in which silencing of the DLC1 gene is due mainly to promoter hypermethylation. Regardless of the epigenetic mechanism of DLC1 inactivation, SAHA treatment of DLC1-transduced cells had a synergistic inhibitory effect on tumor, cell proliferation and tumorigenesis in both cell lines. In 22Rv1 cells, this combination regimen nearly abolished the formation of colonies in semisolid media as a measure of tumorigenicity in vitro. Current in vitro results validate this protocol as a potentially new therapeutic option in certain cancers.