McDermott Center for Human Growth & Development, UT Southwestern Medical Center, Dallas, Texas 75390-8591, USA.
Mol Carcinog. 2010 Feb;49(2):105-13. doi: 10.1002/mc.20594.
In the treatment of colon cancer, the development of resistance to apoptosis is a major factor in resistance to therapy. New molecular approaches to overcome apoptosis resistance, such as selectively upregulating proapoptotic proteins, are needed in colon cancer therapy. In a mouse model with inactivation of the adenomatous polyposis coli (Apc) tumor suppressor gene, reflecting the pathogenesis of most human colon cancers, the gene encoding feminization-1 homolog b (Fem1b) is upregulated in intestinal epithelium following Apc inactivation. Fem1b is a proapoptotic protein that interacts with apoptosis-inducing proteins Fas, tumor necrosis factor receptor-1 (TNFR1), and apoptotic protease activating factor-1 (Apaf-1). Increasing Fem1b expression induces apoptosis of cancer cells, but effects on colon cancer cells have not been reported. Fem1b is a homolog of feminization-1 (FEM-1), a protein in Caenorhabditis elegans that is regulated by proteasomal degradation, but whether Fem1b is likewise regulated by proteasomal degradation is unknown. Herein, we found that Fem1b protein is expressed in primary human colon cancer specimens, and in malignant SW620, HCT-116, and DLD-1 colon cancer cells. Increasing Fem1b expression, by transfection of a Fem1b expression construct, induced apoptosis of these cells. We found that proteasome inhibitor treatment of SW620, HCT-116, and DLD-1 cells caused upregulation of Fem1b protein levels, associated with induction of apoptosis. Blockade of Fem1b upregulation with morpholino antisense oligonucleotide suppressed the proteasome inhibitor-induced apoptosis of these cells. In conclusion, the proapoptotic protein Fem1b is downregulated by the proteasome in malignant colon cancer cells and mediates proteasome inhibitor-induced apoptosis of these cells. Therefore, Fem1b could represent a novel molecular target to overcome apoptosis resistance in therapy of colon cancer.
在结肠癌的治疗中，细胞凋亡抵抗的发展是治疗抵抗的一个主要因素。在结肠癌治疗中需要新的分子方法来克服凋亡抵抗，例如选择性地上调促凋亡蛋白。在一个腺瘤性结肠息肉病（APC）肿瘤抑制基因失活的小鼠模型中，反映了大多数人类结肠癌的发病机制，在 APC 失活后肠上皮中上调了编码雌性化-1 同源物 b（Fem1b）的基因。Fem1b 是一种促凋亡蛋白，与 Fas、肿瘤坏死因子受体-1（TNFR1）和凋亡蛋白酶激活因子-1（Apaf-1）等凋亡诱导蛋白相互作用。增加 Fem1b 的表达可诱导癌细胞凋亡，但尚未报道其对结肠癌细胞的影响。Fem1b 是雌性化-1（FEM-1）的同源物，FEM-1 是秀丽隐杆线虫中的一种蛋白，受蛋白酶体降解调节，但 Fem1b 是否也受蛋白酶体降解调节尚不清楚。在此，我们发现 Fem1b 蛋白在原发性人结肠癌标本中表达，并且在恶性 SW620、HCT-116 和 DLD-1 结肠癌细胞中表达。通过 Fem1b 表达构建体的转染增加 Fem1b 表达，诱导这些细胞凋亡。我们发现蛋白酶体抑制剂处理 SW620、HCT-116 和 DLD-1 细胞导致 Fem1b 蛋白水平上调，与诱导凋亡相关。用 morpholino 反义寡核苷酸阻断 Fem1b 的上调抑制了这些细胞中蛋白酶体抑制剂诱导的凋亡。总之，促凋亡蛋白 Fem1b 在恶性结肠癌细胞中被蛋白酶体下调，并介导这些细胞中蛋白酶体抑制剂诱导的凋亡。因此，Fem1b 可能代表克服结肠癌治疗中细胞凋亡抵抗的新分子靶点。
