FV-429 induces apoptosis and inhibits glycolysis by inhibiting Akt-mediated phosphorylation of hexokinase II in MDA-MB-231 cells
Authors: Chen Qiao
Zhiyu Li
Libin Wei
Ting Ni
Yuxin Zhou
Boyang Yu
Qinglong Guo
Na Lu
Journal: Molecular Carcinogenesis (2016)
Discipline: CLINICAL MEDICINE
Keywords: Akt; FV-429; HKII; breast cancer; mitochondrial-mediated apoptosis.
Affiliations: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China., Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, 639# Long Mian Avenue, Nan Jing, P.R. China.

Abstract:  In this study, the anticancer effect of a newly synthesized flavonoid FV-429, against human breast cancer MDA-MB-231 cells, and the underlying mechanisms were investigated. FV-429 triggered the apoptosis and simultaneously inhibited the glycolysis of MDA-MB-231 cells. Both the HK II activity and its level in mitochondria were significantly down regulated by FV-429. Moreover, FV-429 weakened the interaction between HKII and VDAC, stimulated the detachment of HK II from the mitochondria, and resulted in the opening of the mitochondrial permeability transition pores. Thus FV-429 induced the mitochondrial-mediated apoptosis, showing increased Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP) and activation of caspase-3 and -9, cytochrome c (Cyt c) release, and apoptosis inducing factor (AIF) transposition. Further research revealed that the phosphorylation of mitochondrial HKII via Akt was responsible for the dissociation of HKII and the decreased HKII activity induced by FV-429. Taken together, FV-429 inhibited the phosphorylation of HKII, down-regulated its activity, and stimulated the release of HKII from the mitochondria, resulting the inhibited glycolysis and mitochondrial-mediated apoptosis. The studies provide a molecular basis for the development of flavonoid compounds as novel anticancer agents for breast cancer. ¬© 2015 Wiley Periodicals, Inc. 

Retracted: No

PubPeer comments:
 Figure 3A and 5A: duplication of western blot data:  , 
 An additional problem was found in this article: In Figure 4A two flow cytometry dot plots share surprisingly many data points (please see examples marked in red), but they represent different treatment (FV-429 20 u00b5M vs FV-429 40 u00b5M).  , 
 #2 Two lower panels of Fig 4A:  Re-gating is not a sufficient explanation. , 
 Oops, there s more.  , 
 Figure 1E:  I am intrigued by the two right-hand plots. Unlike the other three cases, the vast majority of cell measurements - falling into the lower left quadrant in each case - have formed distributions with regularly-spaced white lacunae, somewhat resembling strawberries.  That is to say, the cell measurements have swamped every bin within the triangular central zone of the distribution, resulting in a wedge of red. Except for non-randomly-spaced bins, which collected no cells at all, resulting in the white spots within that wedge.   This is not what one expects from stochastic measurements. Does anyone have an explanation for this? , 
 Corrigendum published 28 November 2019 [February 2020] :  In 1 the following error was published on pages 1323 and 1326, respectively.  During the experiment, the authors conducted multiple batches of samples in one gel together, and confused the actin for different batches of samples. Because of the confusion, the authors misplaced the protein actin (COX IV and u03b2u2010actin) of Figure 3A as the protein actin of Figure 5A. In addition, the protein actin in Figure 3A for mitochondrial protein and cytosol protein was placed upside down. COX IV is the actin for mitochondrial protein, and u03b2u2010actin for cytosol protein.    The authors apologize for the mistake. ,