Up-regulation of hexokinaseII in myeloma cells: targeting myeloma cells with 3-bromopyruvate

Abstract

Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. However, HKII levels and its roles in ATP production and ATP-dependent cellular process have not been well studied in hematopoietic malignant cells including multiple myeloma (MM) cells.We demonstrate herein that HKII is constitutively over-expressed in MM cells. 3-bromopyruvate (3BrPA), an inhibitor of HKII, promptly and substantially suppresses ATP production and induces cell death in MM cells. Interestingly, cocultures with osteoclasts (OCs) but not bone marrow stromal cells (BMSCs) enhanced the phosphorylation of Akt along with an increase in HKII levels and lactate production in MM cells. The enhancement of HKII levels and lactate production in MM cells by OCs were mostly abrogated by the PI3K inhibitor LY294002, suggesting activation of glycolysis in MM cells by OCs via the PI3K-Akt-HKII pathway. Although BMSCs and OCs stimulate MM cell growth and survival, 3BrPA induces cell death in MM cells even in cocultures with OCs as well as BMSCs. Furthermore, 3BrPA was able to diminish ATP-dependent ABC transporter activity to restore drug retention in MM cells in the presence of OCs. These results may underpin possible clinical application of 3BrPA in patients with MM.

Hypoxia-inducible KDM3A addiction in multiple myeloma

“…8 To address this in our system, we performed an XTT assay with normoxia and hypoxia in the MM cell line, U266, using the glycolytic inhibitor 3-bromopyruvate. 17 We found that inhibition of glycolysis led to an increase in cell death under hypoxic conditions (supplemental Figure 1B-C), suggesting that glycolysis becomes more important during hypoxia in MM cells. We identified genes whose expression increased more than 2-fold in the examined specimens and performed a gene ontology analysis ( Figure 1A).…”

Regulation of Death Induction and Chemosensitizing Action of 3-Bromopyruvate in Myeloid Leukemia Cells: Energy Depletion, Oxidative Stress, and Protein Kinase Activity Modulation

“…This effect was considered to be a consequence of energy depletion, which could affect ATP-dependent processes such as DNA repair on treatment with DNA-damaging agents (Ihrlund et al, 2008) or pump-mediated drug export in multidrug-resistant (MDR) cells (Xu et al, 2005;Nakano et al, 2012). We combined 3-BrP with the antileukemic agent ATO and the phenolic agent curcumin for the following reasons: 3-BrP causes oxidative stress, and its toxicity is increased on Akt and ERK inhibition (our present results); ATO toxicity is augmented in pro-oxidant environments, either constitutive or experimentally induced ROS elevation (Yi et al, 2002;Díaz et al, 2005) or GSH decrease (Dai et al, 1999;Yang et al, 1999); and phenolic agents such as curcumin frequently downregulate Akt (Lin, 2007;Sánchez et al, 2010).…”

“…It may also induce endoplasmicreticulum stress (Ganapathy-Kanniappan et al, 2010) and autophagy (Davidescu et al, 2012). Furthermore, 3-BrP can reverse multidrug resistance by inhibiting ATP-binding cassette transporter activity (Nakano et al, 2012). However, the capacity of 3-BrP to modulate protein kinase-related signaling pathways that are known to regulate cell death has been poorly studied, and the data available are somewhat conflicting (e.g., Bhardwaj et al, 2010;Lee et al, 2011).…”

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

“…A more recent study demonstrated that 3-BP exerts anti-hepatoma effects, as shown by in vitro and in vivo analyses [62]. In addition, in multiple myeloma (MM) cells, in which HK-II was over-expressed, 3-BP promptly and substantially suppressed adenosine triphosphate production and induced cell death [63]. For endometrial cancer, 3-BP induced tumor necrosis in vitro and inhibited tumor growth in vivo [64].…”