Mycoepoxydiene suppresses HeLa cell growth by inhibiting glycolysis and the pentose phosphate pathway

Abstract

Upregulation of glycolysis and the pentose phosphate pathway (PPP) is a major characteristic of the metabolic reprogramming of cancer and provides cancer cells with energy and vital metabolites to support their rapid proliferation. Targeting glycolysis and the PPP has emerged as a promising antitumor therapeutic strategy. Marine natural products are attractive sources for anticancer therapeutics, as evidenced by the antitumor drug Yondelis. Mycoepoxydiene (MED) is a natural product isolated from a marine fungus that has shown promising inhibitory efficacy against HeLa cells in vitro. We used a proteomic approach with two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry to explore the cellular targets of MED and to unravel the molecular mechanisms underlying the antitumor activity of MED in HeLa cells. Our proteomic data showed that triosephosphate isomerase (TPI) and 6-phosphogluconolactonase (PGLS), which participate in glycolysis and the PPP, respectively, were significantly downregulated by MED treatment. Functional studies revealed that the expression levels of several other enzymes involved in glycolysis and the PPP, including hexokinase 2 (HK2), phosphofructokinase 1 (PFKM), aldolase A (ALDOA), enolase 1 (ENO1), lactate dehydrogenase A (LDHA), and glucose-6-phosphate dehydrogenase (G6PD), were also reduced in a dose-dependent manner. Moreover, the LDHA and G6PD enzymatic activities in HeLa cells were inhibited by MED, and overexpression of these downregulated enzymes rescued HeLa cells from the growth inhibition induced by MED. Our data suggest that MED suppresses HeLa cell growth by inhibiting glycolysis and the PPP, which provides a mechanistic basis for the development of new therapeutics against cervical cancer.

Initial Analysis on the Characteristics and Synthesis of Exopolysaccharides from Sclerotium rolfsii with Different Sugars as Carbon Sources

“…In organisms, different proteins coordinate with one another to perform their biological functions, which can be elucidated by pathway-based analysis [13,29,30]. Some proteins (and genes) that are involved in polysaccharide biosynthesis in bacteria have been identified, but the corresponding pathways in fungus are still unclear [31,32]. Different carbon sources lead to the expression of different proteins, which results in different EPS properties.…”

Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells

“…However, in HL60 and THP1 the incorporation of 13 C from glucose in pentoses of nucleotides moieties upon VEGF exposure indicates that VEGF promotes a switch of glycolysis intermediates towards nucleotides synthesis, possibly through PPP. (Figure 2A and 2B ) Increased rates of PPP is a phenomenon that was recently described in sepsis, when myeloid cells are engaged with proliferation and differentiation [ 19 ] and also in cancer cells [ 20 , 21 ] including leukemia [ 22 ].…”

“…The influence of VEGF in the HL60 metabolic switch of lactate and glucose can be related to cell proliferation as HL60 had a lower duplication time (DT) and cell cycle duration (CCD) in the presence of VEGF in comparison to cells cultured in control conditions and in the presence of lactate (Table 1 , Figure 4A ). Accordingly, several studies have shown that glycolysis rate increases in highly proliferative cells [ 21 , 23 – 25 ] and PI3K/Akt/mTOR pathway is relevant in glycolysis regulation [ 25 , 26 ]. In addition the existence of an autocrine loop of VEGF with its receptor 2 (VEGFR2/KDR) in HL60 cells is well known [ 27 ] and interestingly VEGFR2 can activate PI3K/AkT/mTOR pathway pathway [ 28 , 29 ].…”

Metabonomics analysis of Zi goose follicular granulosa cells using ENO1 gene expression interference

“…ENO1 is expressed in the nucleus and cytoplasm, suggesting the protein plays an important role in FGC development (Cappello, Principe, Bulfamante, & Novelli, ). Cell development requires the participation of glycolysis (Jin et al, ), and ENO1 can affect the glycolysis process (Qian et al, ), so we speculate that interfering with ENO1 may affect the downstream metabolites, thus affecting the development of FGCs. Therefore, it is important to study the effects of ENO1 downstream metabolites on FGCs.…”