Dataset Information

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

ABSTRACT: The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPK?. CYP3A4 knockdown activated AMPK?, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.

SUBMITTER: Guo Z

PROVIDER: S-EPMC5650512 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

Guo Zhijun Z Sevrioukova Irina F IF Denisov Ilia G IG Zhang Xia X Chiu Ting-Lan TL Thomas Dafydd G DG Hanse Eric A EA Cuellar Rebecca A D RAD Grinkova Yelena V YV Langenfeld Vanessa Wankhede VW Swedien Daniel S DS Stamschror Justin D JD Alvarez Juan J Luna Fernando F Galván Adela A Bae Young Kyung YK Wulfkuhle Julia D JD Gallagher Rosa I RI Petricoin Emanuel F EF Norris Beverly B Flory Craig M CM Schumacher Robert J RJ O'Sullivan M Gerard MG Cao Qing Q Chu Haitao H Lipscomb John D JD Atkins William M WM Gupta Kalpna K Kelekar Ameeta A Blair Ian A IA Capdevila Jorge H JH Falck John R JR Sligar Stephen G SG Poulos Thomas L TL Georg Gunda I GI Ambrose Elizabeth E Potter David A DA

Cell chemical biology 20170914 10

The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis ...[more]

PMID: 28919040

Similar Datasets

Project description:BackgroundHepatic steatosis is an early pathology of alcohol-associated liver disease (ALD). Fatty acid-binding protein-4 (FABP4, a FABP not normally produced in the liver) is secreted by hepatocytes in ALD and stimulates hepatoma proliferation and migration. This study sought to investigate the mechanism[s] by which hepatic ethanol metabolism regulates FABP4 and steatosis.MethodsHuman hepatoma cells (HepG2/HuH7) and cells stably transfected to express cytochrome P450 2E1 (CYP2E1), were exposed to ethanol in the absence or presence of chlormethiazole (a CYP2E1-inhibitor; CMZ) and/or EX-527 (a sirtuin-1 [SIRT1] inhibitor). The culture medium was analyzed for ethanol metabolism and FABP4 protein abundance. Cells were analyzed for FABP4 mRNA expression, SIRT1 protein abundance, and neutral lipid accumulation. In parallel, cells were analyzed for forkhead box O1 [FOXO1], β-catenin, peroxisome proliferator-activated receptor-α [PPARα], and lipin-1α protein abundance in the absence or presence of ethanol and pharmacological inhibitors of the respective target proteins.ResultsCYP2E1-dependent ethanol metabolism inhibited the amount of SIRT1 protein detected, concomitant with increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation, effects abolished by CMZ. Analysis of pathways associated with lipid oxidation revealed increased FOXO1 nuclear localization and decreased β-catenin, PPARα, and lipin-1α protein levels in CYP2E1-expressing cells in the presence of ethanol. Pharmacological inhibition of SIRT1 mimicked the effects of ethanol, while inhibition of FOXO1 abrogated the effect of ethanol on FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation in CYP2E1-expressing cells. Pharmacological inhibition of β-catenin, PPARα, or lipin-1α failed to alter the effects of ethanol on FABP4 or neutral lipid accumulation.ConclusionCYP2E1-dependent ethanol metabolism inhibits SIRT1-FOXO1 signaling, which leads to increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation. These data suggest that FABP4 released from steatotic hepatocytes could play a role in promoting tumor cell expansion in the setting of ALD and represents a potential target for therapeutic intervention.

Dataset Information

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

Publications

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets