BH3 profiling discriminates the anti-apoptotic status of 5-fluorouracil-resistant colon cancer cells
BH3 profiling discriminates the anti-apoptotic status of 5-fluorouracil-resistant colon cancer cells
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DOI：
10.3892/or.2019.7373
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发表时间：
2019-12-01
期刊：
影响因子：
4.2
通讯作者：
Kato, Junji
中科院分区：
文献类型：
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作者：
Ishikawa, Kazuma;Kawano, Yutaka;Kato, Junji
5-氟尿嘧啶（5-FU）是一种细胞毒性抗癌药物，常用于晚期结肠癌患者。这种药物可以在一定程度上有效地缩小肿瘤的大小；然而，癌细胞会逐渐获得抵抗力，导致疾病进展。为了确定 5-FU 耐药机制，我们建立了三种 5-FU 耐药结肠癌细胞系，并分析了凋亡相关蛋白表达水平和 BH3 谱。这些 5-FU 抗性结肠癌细胞系获得了对 5-FU 的凋亡抗性。尽管凋亡相关蛋白表达水平在每种 5-FU 耐药性结肠癌细胞系中发生不同程度的改变，但 BH3 分析表明仅在 5-FU 耐药性 HT-29 细胞中存在 BCLXL 依赖性。 5-FU 耐药 HT-29 细胞中的功能性 BCLXL 抑制不仅使细胞对凋亡敏感，而且还克服了 5-FU 耐药。凋亡的 BIM 蛋白优先被隔离，从而导致对 BCLXL 的生存依赖。此外，体内模型表明 BCLXL 抑制可控制肿瘤进展。这些结果表明，BH3 分析有助于识别抗凋亡蛋白在耐药过程中的功能作用，并且对靶向 BCLXL 等特定蛋白的结肠癌具有临床意义。
5-Fluorouracil (5-FU) is a cytotoxic anticancer drug commonly used for patients with advanced colon cancer. This drug effectively reduces the size of tumors to a certain degree; however, cancer cells can gradually acquire resistance, resulting in disease progression. To identify the mechanism of 5-FU resistance, we established three 5-FU-resistant colon cancer cell lines and analyzed both apoptosis-related protein expression levels and BH3 profiling. These 5-FU-resistant colon cancer cell lines acquired apoptotic resistance to 5-FU. Although apoptosis-related protein expression levels were altered in each 5-FU-resistant colon cancer cell line variably, BH3 profiling indicated BCLXL dependence in 5-FU-resistant HT-29 cells only. Functional BCLXL inhibition in 5-FU-resistant HT-29 cells not only sensitized the cells to apoptosis but also overcame 5-FU resistance. The apoptotic BIM protein was preferentially sequestered, thereby resulting in acquired dependence on BCLXL for survival. Additionally, in vivo models showed that BCLXL inhibition controlled tumor progression. These results indicate that BH3 profiling facilitates the identification of the functional role of anti-apoptotic proteins during drug resistance and has clinical implications for colon cancer in targeting specific proteins such as BCLXL.