University of Rijeka Department of Biotechnology, Centre for High-Throughput Technologies, Radmile Matejčić 2, 51000 Rijeka, Croatia.
University of Rijeka Faculty of Medicine, Department for General Pathology and Pathologic Anatomy, Braće Branchetta 20, 51000 Rijeka, Croatia.
Biochem Biophys Res Commun. 2018 Sep 5;503(2):843-848. doi: 10.1016/j.bbrc.2018.06.085. Epub 2018 Jun 21.
Acid ceramidase (ASAH1) has been implicated in the progression and chemoresistance in different cancers. Its role in colon cancer biology and response to standard chemotherapy has been poorly addressed so far. Here, we have investigated ASAH1 expression at the protein level in human colon cancer cell lines and tissues from colon cancer patients, and have examined in vitro the possible link between ASAH1 expression and functional activity of p53 protein whose inactivation is associated with the progression from adenoma to malignant tumour in colon cancer. Finally, we have explored the role of ASAH1 in response and resistance mechanisms to oxaliplatin (OXA) in HCT 116 colon cancer cells. We have demonstrated that human colon cancer cells and colorectal adenocarcinoma tissues constitutively express ASAH1, and that its expression is higher in tumour tissues than in normal colonic mucosa. Furthermore, we found an inverse correlation between ASAH1 expression and p53 functional activity. Obtained data revealed that ASAH1 was involved in HCT 116 cell response to OXA and that anti-proliferative, pro-apoptotic, anti-migratory and anti-clonogenic effects of OXA could be significantly increased by combination treatment with ASAH1 inhibitor carmofur. Increased OXA sensitivity was associated with downregulation of signalling involved in acquired resistance to OXA in colon cancer, in particular transglutaminase 2 and β1 integrin/FAK, which resulted in the suppression of NF-κB and Akt. Thus, combination of OXA with ASAH1 inhibitors could be a promising strategy to counter chemoresistance and improve treatment outcome in advanced colon cancer.
酸性鞘氨醇酶（ASAH1）已被牵连到不同癌症的进展和化疗耐药性中。到目前为止，其在结肠癌生物学和对标准化疗的反应中的作用仍未得到充分解决。在这里，我们研究了人结肠癌细胞系和结肠癌患者组织中 ASAH1 的蛋白水平表达，并研究了 ASAH1 表达与 p53 蛋白功能活性之间的可能联系，p53 蛋白失活与结肠癌从腺瘤向恶性肿瘤的进展有关。最后，我们探索了 ASAH1 在 HCT 116 结肠癌细胞对奥沙利铂（OXA）的反应和耐药机制中的作用。我们已经证明，人结肠癌细胞和结直肠腺癌组织中持续表达 ASAH1，并且在肿瘤组织中的表达高于正常结肠黏膜。此外，我们发现 ASAH1 表达与 p53 功能活性呈负相关。获得的数据表明，ASAH1 参与了 HCT 116 细胞对 OXA 的反应，并且 OXA 的抗增殖、促凋亡、抗迁移和抗集落形成作用可以通过与 ASAH1 抑制剂卡莫氟联合治疗显著增加。增加 OXA 的敏感性与结肠癌中获得性 OXA 耐药相关信号的下调有关，特别是转谷氨酰胺酶 2 和β1 整合素/FAK，这导致 NF-κB 和 Akt 的抑制。因此，OXA 与 ASAH1 抑制剂的联合使用可能是一种有前途的策略，可以克服化学耐药性并改善晚期结肠癌的治疗效果。
