Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain.
J Biosci. 2021;46.
Advanced-stage gastrointestinal tumors have high mortality due to chemotherapy limitations. One of the causes of treatment failure is the presence of cancer stem cells (CSCs), which show resistance mechanisms against DNA damage, such as poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1). However, little is known about the relevance of PARP-1 in these tumor cells. Our purpose is to analyze the expression of PARP-1 in cancer cells and CSCs from gastrointestinal tumors, its relationship with the DNA damage repair process and its modulation by cytotoxic and PARP-1 inhibitors. We used pancreatic, liver and colon cancer cell lines and isolated CSCs using Aldefluor technology to analyze PARP-1 expression. In addition, we examined the effect of classic cytotoxic drugs (Doxorubicin, Gemcitabine, Irinotecan and 5-Fluorouracil) and a PARP-1 inhibitor (Olaparib) in cultured cells and 3D tumorspheres. We demonstrated that PARP-1 is highly expressed in pancreatic, liver and colon tumor cells and that this expression was significantly higher in cell populations with CSC characteristics. In addition, Doxorubicin and Gemcitabine increased their cytotoxic effect when administered simultaneously with Olaparib, decreasing the formation of 3D tumorspheres. Our findings suggest that PARP-1 is a common and relevant resistance mechanism in CSCs from gastrointestinal tumors and that the use of PARP-1 inhibitors may be an adjuvant therapy to increase apoptosis in this type of cells which are responsible to cancer recurrence and metastasis.
晚期胃肠道肿瘤由于化疗的局限性而导致死亡率较高。治疗失败的原因之一是存在癌症干细胞 (CSC)，它们对 DNA 损伤具有抵抗机制，例如聚（腺苷二磷酸核糖）聚合酶 1 (PARP-1)。然而，人们对这些肿瘤细胞中 PARP-1 的相关性知之甚少。我们的目的是分析胃肠道肿瘤的癌细胞和 CSC 中 PARP-1 的表达，其与 DNA 损伤修复过程的关系以及细胞毒性和 PARP-1 抑制剂对其的调节。我们使用胰腺、肝和结肠癌细胞系，并使用 Aldefluor 技术分离 CSC 来分析 PARP-1 的表达。此外，我们还检查了经典细胞毒性药物（阿霉素、吉西他滨、伊立替康和 5-氟尿嘧啶）和 PARP-1 抑制剂（奥拉帕利）在培养细胞和 3D 肿瘤球体中的作用。我们证明 PARP-1 在胰腺、肝和结肠肿瘤细胞中高度表达，并且在具有 CSC 特征的细胞群体中表达显著更高。此外，阿霉素和吉西他滨与奥拉帕利联合使用时增加了它们的细胞毒性作用，减少了 3D 肿瘤球体的形成。我们的研究结果表明，PARP-1 是胃肠道肿瘤 CSC 中常见且相关的耐药机制，PARP-1 抑制剂的使用可能是辅助治疗的一种手段，可增加此类细胞的细胞凋亡，这些细胞是癌症复发和转移的罪魁祸首。
