Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis.
Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis.
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作者：
癌症化学预防使用天然、合成或生物物质来逆转、抑制或预防癌发生的初始阶段或肿瘤细胞向癌症的进展。它有望克服与晚期癌症治疗相关的问题。然而，目前化学预防的广泛应用受到有限有效性和潜在毒性的影响。为了克服这些挑战，我们开发了一种新的化学预防方法，专门针对癌前肿瘤细胞的凋亡。我们发现，腺瘤性结肠息肉病（APC）基因的缺陷和随后的β-连环蛋白的激活通过激活c-Myc导致细胞caspase-8抑制剂c-FLIP（也称为CFLAR）表达的抑制，并且全反式-乙酸视黄酯（RAc）独立上调肿瘤坏死因子相关凋亡诱导配体（TRAIL）死亡受体并抑制诱饵受体。因此，TRAIL和RAc的组合诱导APC缺陷的癌前细胞的凋亡，而不影响正常细胞在体外。此外，我们表明，短期和非连续的TRAIL和RAc治疗诱导细胞凋亡，特别是在肠息肉，强烈抑制肿瘤生长，并延长生存在多种肠肿瘤C57 BL/6 J-ApcMin/J（ApcMin）小鼠。通过我们的方法，我们进一步证明了TRAIL和RAc在人结肠息肉中诱导显著的细胞死亡，通过靶向APC缺陷细胞进行凋亡，为结直肠癌化学预防提供了一种潜在的选择性方法。
Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of β-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cellsin vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-ApcMin/J (ApcMin) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.
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影响因子：
3.5
作者：
Bai, Xiaowen;Sadat, Sanga;Song, Yao-Hua
通讯作者：
Song, Yao-Hua
影响因子：
3.5
作者：
Hasson, E;Slovatizky, Y;Mitrani, E
通讯作者：
Mitrani, E
影响因子：
56.9
作者：
MOSER, AR;PITOT, HC;DOVE, WF
通讯作者：
DOVE, WF
影响因子：
32.4
作者：
Wiley, SR;Schooley, K;Goodwin, RG
通讯作者：
Goodwin, RG
DOI：
10.1073/pnas.91.19.8969
发表时间：
1994-09-13
影响因子：
11.1
作者：
FODDE, R;EDELMANN, W;KUCHERLAPATI, R
通讯作者：
KUCHERLAPATI, R