Department of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of A Dietary, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Clin Exp Pharmacol Physiol. 2022 Dec;49(12):1334-1341. doi: 10.1111/1440-1681.13718. Epub 2022 Sep 29.
Imatinib, an inhibitor of tyrosine kinase, shows remarkable efficacy in chronic myeloid leukaemia (CML). Autophagy protects tumour cells against chemotherapeutic stimulation and contributes to imatinib resistance in CML. Kinesin family member 23 (KIF23) is involved in cytokinesis and associated with autophagy. The role of KIF23 in autophagy-induced imatinib resistance in CML was investigated. First, to induce drug resistance, CML cells were exposed to increasing concentrations of imatinib. The concentration of imatinib resistance in CML cells was screened through upregulation of 50% inhibitory concentration (IC ) values. KIF23 was elevated in imatinib-resistant tissues and cells of CML. Second, knockdown of KIF23 reduced IC values of imatinib-resistant CML cells to imatinib. Moreover, silence of KIF23 also suppressed cell proliferation and promoted apoptosis of imatinib-resistant CML cells. Third, immunofluorescence analysis showed that the number of LC3 bright spots in imatinib-resistant CML cells was reduced by silence of KIF23. Knockdown of KIF23 upregulated p62 expression and downregulated the expression ratio of LC3-II to LC3-I in imatinib-resistant CML cells. Last, silence of KIF23 decreased nuclear β-catenin and increased cytoplasmic β-catenin in imatinib-resistant CML cells. Activator of Wnt/β-catenin attenuated KIF23 silence-induced increase of apoptosis and decrease of autophagy in imatinib-resistant CML cells. In conclusion, loss of KIF23 repressed autophagy-induced imatinib resistance in CML cells through inactivation of Wnt/β-catenin pathway.
伊马替尼是一种酪氨酸激酶抑制剂，在慢性髓性白血病（CML）中显示出显著的疗效。自噬可保护肿瘤细胞免受化疗刺激，并导致 CML 中伊马替尼耐药。驱动蛋白家族成员 23（KIF23）参与细胞分裂，与自噬有关。本研究探讨了 KIF23 在 CML 中自噬诱导的伊马替尼耐药中的作用。首先，为了诱导耐药，将 CML 细胞暴露于递增浓度的伊马替尼中。通过上调 50%抑制浓度（IC）值筛选 CML 细胞对伊马替尼的耐药浓度。KIF23 在伊马替尼耐药的 CML 组织和细胞中上调。其次，敲低 KIF23 降低了伊马替尼耐药的 CML 细胞对伊马替尼的 IC 值。此外，沉默 KIF23 还抑制了伊马替尼耐药的 CML 细胞的增殖并促进了其凋亡。第三，免疫荧光分析显示，沉默 KIF23 减少了伊马替尼耐药的 CML 细胞中 LC3 亮点的数量。沉默 KIF23 可上调 p62 表达并下调伊马替尼耐药的 CML 细胞中 LC3-II 与 LC3-I 的表达比值。最后，沉默 KIF23 减少了伊马替尼耐药的 CML 细胞中的核β-catenin 并增加了细胞质中的β-catenin。Wnt/β-catenin 激活剂可减弱 KIF23 沉默诱导的伊马替尼耐药的 CML 细胞中的凋亡增加和自噬减少。综上所述，KIF23 的缺失通过抑制 Wnt/β-catenin 通路抑制了 CML 细胞中自噬诱导的伊马替尼耐药。
