Research Papers:

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 spatially mediates autophagy through the AMPK signaling pathway

Siyuan Yan, Xiaoli Wei, Shanshan Xu, Hui Sun, Weijun Wang, Ling Liu, Xuejun Jiang, Yongxiang Zhang and Yongsheng Che _

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Oncotarget. 2017; 8:80909-80922. https://doi.org/10.18632/oncotarget.20757

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Siyuan Yan1,3, Xiaoli Wei2, Shanshan Xu1,3, Hui Sun1,3, Weijun Wang1,3, Ling Liu1, Xuejun Jiang1, Yongxiang Zhang2 and Yongsheng Che2

1State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China

2State Key Laboratory of Toxicology & Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China

3University of Chinese Academy of Sciences, Beijing 100039, China

Correspondence to:

Yongsheng Che, email: [email protected]

Yongxiang Zhang, email: [email protected]

Keywords: PFKFB3, glycolysis, nuclear localization, autophagy, AMPK

Received: June 06, 2017     Accepted: August 06, 2017     Published: September 08, 2017


6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), is a critical enzyme for glycolysis and highly expressed in cancer cells. It plays an essential role in regulating metabolism, angiogenesis, and inflammation. Although PFKFB3 is involved in modulating autophagy, its regulatory role appears to be either positive or negative, which remains to be clarified. Unlike other PFK-2/FBPase isoforms, PFKFB3 can localize in both nucleus and cytoplasm, leading to the speculation that subcellular localization of PFKFB3 may play a regulatory role in autophagy. Here, we found that either a PFKFB3 inhibitor or PFKFB3 silencing by siRNA, suppressed the basal and the H2O2-induced autophagy concomitantly with the inhibition of AMPK activity. While overexpression of the wild type PFKFB3 promoted the H2O2-induced autophagy, the K472/473A mutated PFKFB3, which lost nuclear localizing property, inhibited the autophagic process. Although the K472/473A mutated PFKFB3 stimulated more lactate production, it decreased the activity of AMPK compared to the wild type PFKFB3. Moreover, PFKFB3 similarly regulates the autophagy induced by rasfonin, a fungal secondary metabolite that downregulates the activity of AMPK. Compound C, a widely used AMPK inhibitor, induced the autophagic process but reduced the H2O2-dependent autophagy. Collectively, the data demonstrated that PFKFB3 localizing in nucleus is essential for its regulatory role in autophagy, and PFKFB3 at least positively regulated the H2O2-induced autophagy through the AMPK signaling pathway, which likely played dual roles in the process.

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