Anti-cancer fatty-acid derivative induces autophagic cell death through modulation of PKM isoform expression profile mediated by bcr-abl in chronic myeloid leukemia

Shinohara, Haruka; Taniguchi, Kohei; Kumazaki, Minami; Yamada, Nami; Ito, Yuko; Otsuki, Yoshinori; Uno, Bunji; Hayakawa, Fumihiko; Minami, Yosuke; Naoe, Tomoki; Akao, Yukihiro

doi:10.1016/j.canlet.2015.01.039

Cited by 49 publications

(55 citation statements)

References 29 publications

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“…Our results demonstrate that ABTL0812 induces autophagy-mediated cancer cell death in vitro and in vivo, without activating cellular apoptosis. These results are in agreement with those reporting that polyunsaturated fatty acid and derivatives exert their antiproliferative action through activation of autophagy (21)(22)(23).…”

Section: Discussionsupporting

confidence: 93%

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

Erazo

Lorente

López-Plana

et al. 2016

Clinical Cancer Research

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Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development.Experimental Design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database.Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARa and PPARg as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARa/g or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial.Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARa/g-TRIB3-AktmTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy.

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Section: Discussionsupporting

confidence: 93%

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

Erazo

Lorente

López-Plana

et al. 2016

Clinical Cancer Research

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“…Kinome profiling provided us with a global overview of kinase activity that accompanies the acquisition of multidrug resistance. Shinohara et al (2015) have reported that a higher activity of Src kinase promotes PKM2 inhibition. Accordingly, kinome profiling and pulldown experiments also revealed that PAK1 is more active in resistant leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

Oncophosphosignaling Favors a Glycolytic Phenotype in Human Drug Resistant Leukemia

Faria

Tornatore

Milani

et al. 2017

J of Cellular Biochemistry

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In chemoresistant leukemia cells (Lucena-1), the low molecular weight protein tyrosine phosphatase (LMWPTP) is about 20-fold more active than in their susceptible counterpart (K562). We found this phosphatase ensures the activated statuses of Src and Bcr-Abl. Since, phosphorylation and dephosphorylation of proteins represent a key post-translational regulation of several enzymes, we also explored the kinome. We hereby show that LMWPTP superactivation, together with kinome reprogramming, cooperate towards glucose addiction. Resistant leukemia cells present lower levels of oxidative metabolism, in part due to downexpression of the following mitochondrial proteins: pyruvate dehydrogenase subunit alpha 1, succinate dehydrogenase, and voltage-dependent anion channel. Those cells displayed higher expression levels of glucose transporter 1 and higher production of lactate. In addition, Lucena-1 siRNA LMWPTP cells showed lower expression levels of glucose transporter 1 and lower activity of lactate dehydrogenase. On the other hand, K562 cells overexpressing LMWPTP presented higher expression/activity of both proteins. In this study, we show that LMWPTP is a pivotal mediator of metabolic reprogramming that confers survival advantages to leukemia cells against death stimuli. J. Cell. Biochem. 118: 3846-3854, 2017. © 2017 Wiley Periodicals, Inc.

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“…Histone H3 was used as a control for nuclear protein, and GAPDH was used as a control for cytoplasmic protein. Also, β‐actin served as an indicator for contamination of cytoplasmic proteins into the nuclear fraction …”

Section: Methodsmentioning

confidence: 99%

Oncogene RNA helicase DDX6 promotes the process of c‐Myc expression in gastric cancer cells

Taniguchi

Iwatsuki

Sugito

et al. 2018

Molecular Carcinogenesis

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Human DEAD-box RNA helicase gene DDX6 was cloned from B-cell lymphoma cell line RC-K8. Previously, we reported that DDX6 acts as oncogene in several cancers such as colorectal cancer and hepatocellular carcinoma. However, the detailed mechanism of DDX6 action in carcinogenesis is largely unknown. In this study, we examined the functions of DDX6 in clinical gastric cancer (GC) samples and GC cells. DDX6 protein expression levels of cancer samples were higher than those of the adjacent normal tissues in 25 clinical GC samples (median value: 1.4 times higher). Also, the results of an RNA immunoprecipitation-assay (RIP-assay) showed that DDX6 associated with c-Myc mRNA. Moreover, enforced overexpression of DDX6 promoted both mRNA and protein expression of c-Myc in GC cells. On the other hand, the gene silencing of DDX6 induced growth suppression through down-regulation of c-Myc in GC cells grown in either two or three dimensions. Furthermore, c-Myc mRNA expression levels of cancer samples were higher than those of the adjacent normal tissues in DDX6 up-regulated-GC clinical samples. Our findings in this study suggested that DDX6 acted as oncogene in GC cells through promotion of c-Myc expression by association with the mRNA of c-Myc.

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Anti-cancer fatty-acid derivative induces autophagic cell death through modulation of PKM isoform expression profile mediated by bcr-abl in chronic myeloid leukemia

Cited by 49 publications

References 29 publications

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

Oncophosphosignaling Favors a Glycolytic Phenotype in Human Drug Resistant Leukemia

Oncogene RNA helicase DDX6 promotes the process of c‐Myc expression in gastric cancer cells

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