1. Academic Validation
  2. AICAR enhances the cytotoxicity of PFKFB3 inhibitor in an AMPK signaling-independent manner in colorectal cancer cells

AICAR enhances the cytotoxicity of PFKFB3 inhibitor in an AMPK signaling-independent manner in colorectal cancer cells

  • Med Oncol. 2021 Nov 10;39(1):10. doi: 10.1007/s12032-021-01601-y.
Siyuan Yan 1 Dongdong Yuan 2 Qianqian Li 3 Shi Li 3 Fan Zhang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Precision Oncology in Universities of Shandong, Institute of Precision Medicine, Jining Medical University, Jining, 272067, China. yansy@mail.jnmc.edu.cn.
  • 2 Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China.
  • 3 Key Laboratory of Precision Oncology in Universities of Shandong, Institute of Precision Medicine, Jining Medical University, Jining, 272067, China.
  • 4 Department of Bone and Soft Tissue Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, China. zhangfan_1109@163.com.
Abstract

Numerous studies have shown that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), a pivotal Enzyme in modulating glycolysis, plays vital roles in various physiological processes. PFKFB3 activity could be regulated by several factors, such as hypoxia and AMPK signaling; however, it could also function as upstream of AMPK signaling. Here, we showed that PFKFB3 inhibitor PFK-15 induced cell viability loss and Apoptosis. Deprivation of PFKFB3 inhibited Autophagy, while enhanced the ubiquitin-proteasome degradation pathway. Furthermore, PFK-15 reduced both the AMPK and AKT-mTORC1 signaling pathways, as the attenuated phosphorylation level of kinases themselves and their substrates. The addition of AICAR rescued the AMPK activity and Autophagy, but enhanced PFK-15-induced cell viability loss. In fact, AICAR promoted the cytotoxicity of PFK-15 even in the AMPKα1/2-silenced cells, indicating AICAR might function in an AMPK-independent manner. Nevertheless, AICAR further reduced the AKT-mTORC1 activity down-regulated by PFK-15. Moreover, it failed to enhance PFK-15's cytotoxicity in the Akt1/2-silenced cells, indicating AKT-mTORC1 participated during these processes. Collectively, the presented data demonstrated that PFK-15 inhibited cell viability, AMPK, and AKT-mTORC1 signaling, and AICAR probably enhanced the cell viability loss aroused by PFK-15 in an AKT-dependent and AMPK-independent manner, thereby revealing a more intimate relationship among PFKFB3, AMPK, and AKT-mTORC1 signaling pathways.

Keywords

AICAR; AMPK signaling; Cell viability; Colorectal cancer; PFKFB3.

Figures
Products