Li Qianqian, Ma Jianxing, Zhang Yaqin, Sun Fengyao, Li Wen, Shen Wenzhi, Ai Zhiying, Li Changli, Wang Shanshan, Wei Xiaonan, Yan Siyuan
Shandong Provincial Precision Medicine Laboratory for Chronic Non-communicable Diseases, Institute of Precision Medicine, Jining Medical University, Jining, China.
Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Front Pharmacol. 2024 Sep 4;15:1433137. doi: 10.3389/fphar.2024.1433137. eCollection 2024.
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) is highly expressed in several cancers and plays important roles during the whole pathological process of cancer. It is also involved in chemoresistance, while the intrinsic mechanism needs to be further revealed.
The different responses to cisplatin (DDP) between wild type (WT) and DDP-resistant (DDR) colorectal cancer (CRC) cells were analyzed by several assays. Coumarin conjugated DDP (CP-DDP) was utilized to trace the distribution of DDP. Pharmacological and genetic methods were used to deprive autophagy and PFKFB3, and the effects were investigated. The mouse xenograft model was performed to confirm the effect of the PFKFB3 inhibitor on reversing DDP resistance.
DDR cells showed a lower capacity for apoptosis upon DDP treatment, but exhibited higher levels of autophagy and PFKFB3. CP-DDP partly co-localized with LC3, and its content lessened faster in DDR cells. Deprivation of both autophagy and PFKFB3 attenuated CP-DDP elimination, and reversed the DDP resistance. Moreover, PFKFB3 inhibition reduced DDP-induced autophagy. PFKFB3 inhibitor in combination with DDP led to a remarkable reduction in tumor growth .
Inhibition of PFKFB3 reduced the autophagy induced by DDP, and therefore extended the retention time of CP-DDP. Meanwhile, PFKFB3 deprivation reversed the DDP resistance and made it a potent therapeutic target for CRC.
6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶同工型3（PFKFB3）在多种癌症中高表达，在癌症的整个病理过程中发挥重要作用。它还与化疗耐药性有关，但其内在机制仍需进一步揭示。
通过多种检测方法分析野生型（WT）和耐顺铂（DDR）结直肠癌（CRC）细胞对顺铂（DDP）的不同反应。利用香豆素偶联顺铂（CP-DDP）追踪顺铂的分布。采用药理学和遗传学方法抑制自噬和PFKFB3，并研究其效果。建立小鼠异种移植模型以证实PFKFB3抑制剂对逆转DDP耐药性的作用。
DDR细胞在DDP处理后凋亡能力较低，但自噬水平和PFKFB3水平较高。CP-DDP与LC3部分共定位，其在DDR细胞中的含量下降更快。抑制自噬和PFKFB3均可减弱CP-DDP的清除，并逆转DDP耐药性。此外，抑制PFKFB3可降低DDP诱导的自噬。PFKFB3抑制剂与DDP联合使用可显著抑制肿瘤生长。
抑制PFKFB3可降低DDP诱导的自噬，从而延长CP-DDP的保留时间。同时，抑制PFKFB3可逆转DDP耐药性，使其成为CRC的有效治疗靶点。
