Ravi Rajani, Bedi Atul
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1000, USA.
Cancer Res. 2002 Mar 15;62(6):1583-7.
The cornerstone of the systemic treatment of advanced colorectal cancer is 5-fluorouracil.However, 5-fluorouracil-induced apoptosis is dependent on p53, a tumor suppressor gene that is lost or inactivated in at least 85% of human colorectal cancers. Here we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L triggers caspase-8-mediated truncation of BID, mitochondrial activation of caspase-9, and apoptosis in both p53(+/+) or p53(-/-) isogenic HCT116 colorectal cancer cells. TRAIL/Apo2L also sensitizes both p53(+/+) or p53(-/-) colorectal cancer cells to ionizing radiation. In contrast, we find that TRAIL/Apo2L fails to activate caspase-9 or induce apoptosis in isogenic HCT116 colorectal cancer cells that are deficient in BAX, a proapoptotic gene that is mutated in >50% of colorectal cancers of the microsatellite mutator phenotype. Loss of BAX also renders colorectal cancer cells resistant to TRAIL/Apo2L-mediated radiosensitization. We additionally demonstrate that TRAIL/Apo2L-induced death of p53(+/+)- or p53(-/-)- BAX-proficient but not BAX-deficient colorectal cancer cells is augmented by reducing nuclear factor-kappaB-dependent expression of Bcl-x(L) with either a peptide that disrupts the inhibitor of kappaB kinase complex or the nonsteroidal anti-inflammatory drug, sulindac sulfide. These results indicate that the combination of TRAIL/Apo2L with either irradiation or sulindac may be highly effective against both p53-proficient and p53-deficient colorectal cancers; however, BAX-deficient tumors may evade elimination by TRAIL/Apo2L-based regimens. Our findings may aid the development and genotype-specific application of TRAIL/Apo2L-based combinatorial regimens for the treatment of colorectal cancers.
5-氟尿嘧啶是晚期结直肠癌全身治疗的基石。然而，5-氟尿嘧啶诱导的细胞凋亡依赖于p53，p53是一种肿瘤抑制基因，在至少85%的人类结直肠癌中缺失或失活。在此我们表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）/Apo2L在p53(+/+)或p53(-/-)同基因HCT116结直肠癌细胞中触发胱天蛋白酶-8介导的BID截短、胱天蛋白酶-9的线粒体激活以及细胞凋亡。TRAIL/Apo2L还使p53(+/+)或p53(-/-)结直肠癌细胞对电离辐射敏感。相比之下，我们发现TRAIL/Apo2L在BAX缺陷的同基因HCT116结直肠癌细胞中无法激活胱天蛋白酶-9或诱导细胞凋亡，BAX是一种促凋亡基因，在超过50%的微卫星突变体表型的结直肠癌中发生突变。BAX的缺失也使结直肠癌细胞对TRAIL/Apo2L介导的放射增敏产生抗性。我们还证明，通过用破坏κB激酶复合物抑制剂的肽或非甾体抗炎药舒林酸硫化物降低核因子-κB依赖性Bcl-x(L)的表达，可增强TRAIL/Apo2L诱导的p53(+/+)或p53(-/-)且BAX功能正常而非BAX缺陷的结直肠癌细胞的死亡。这些结果表明，TRAIL/Apo2L与放疗或舒林酸联合使用可能对p53功能正常和p53缺陷的结直肠癌均具有高效性；然而，BAX缺陷的肿瘤可能逃避基于TRAIL/Apo2L的治疗方案的清除。我们的发现可能有助于基于TRAIL/Apo2L的联合治疗方案的开发及其针对结直肠癌治疗的基因型特异性应用。
