Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2

Abstract

We recently reported that shikonin and its analogs were a class of necroptotic inducers that could bypass cancer drug resistance. However, the molecular targets of shikonin are not known. Here, we showed that shikonin and its analogs are inhibitors of tumor-specific pyruvate kinase-M2 (PKM2), among which shikonin and its enantiomeric isomer alkannin were the most potent and showed promising selectivity, that is, shikonin and alkannin at concentrations that resulted in over 50% inhibition of PKM2 activity did not inhibit PKM1 and pyruvate kinase-L (PKL). Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x L and A549) that primarily express PKM2. HeLa cells transfected with PKM1 showed reduced sensitivity to shikonin-or alkannin-induced cell death. To the best of our knowledge, shikonin and alkannin are the most potent and specific inhibitors to PKM2 reported so far. As PKM2 universally expresses in cancer cells and dictates the last rate-limiting step of glycolysis vital for cancer cell proliferation and survival, enantiomeric shikonin and alkannin may have potential in future clinical application.

Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming

“…SKN, a potent PKM2 inhibitor, which has previously been reported to limit glycolysis in tumor cells and protect mice from sepsis through the inhibition of PKM2 in macrophages (18,30), was used in this study. Our in vitro and in vivo experiments demonstrate that SKN inhibits the Hcy-induced upregulation of PKM2 enzyme activity and metabolic reprogramming, leading to the prevention of Hcy-induced B cell proliferation and Ab secretion.…”

“…To verify the potential role of PKM2 in regulating Hcyinduced metabolic changes and B cell activation, the potent PKM2 inhibitor SKN was used. SKN can selectively inhibit the glycolytic enzyme activity of PKM2 without affecting other pyruvate isoforms and may limit the subsequent lactate production and oxidative metabolism in mitochondria (30). We first performed a dose titration of SKN to determine the optimal dose for our experiments.…”

Activation of JNK/p38 Pathway is Responsible for α-Methyl-n-butylshikonin Induced Mitochondria-Dependent Apoptosis in SW620 Human Colorectal Cancer Cells

“…α-Methyl-n-butylshikonin (MBS), one of the shikonin derivatives, is a naphthoquinone pigment isolated from the traditional medical herbs Lithospermum erythrorhizon ( Figure 1A) (Chen et al, 2011). Previous studies have demonstrated that shikonin and its derivatives possess multiple biological functions such as anti-microbial, antiinflammatory, anti-HIV and anti-platelet effects (Tanaka et al, 1986;Ko et al, 1995;Shen et al, 2002;Chen et al, 2003).…”

Envolvimento da enzima Piruvato Quinase M2 (PKM2) na diferenciação de linfócitos Th17 e patogênese da encefalomielite autoimune experimental

“…Shikonin (Sigma-Aldrich), um inibidor da PKM2, foi utilizado em experimentos in vitro e in vivo (CHEN et al, 2011). In vitro, shikonin foi adicionado às culturas de linfócitos T nas concentrações de 0.3, 1 e 3 µM.…”

“…Shikonin foi descrito como um potente inibidor da PKM2 em células tumorais e macrófagos (CHEN et al, 2011;YANG et al, 2014b). Sabendo que os níveis de expressão de PKM2 e fosfo-PKM2 estão aumentados durante a diferenciação de linfócitos Th17, avaliou-se qual a consequência da inibição farmacológica de PKM2 sobre a geração destas células.…”