摘要 : <![CDATA[<ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" xmlns="http://www.elsevier.com/xml/ja/dtd" id="abs0010" view="all" class="author"><ce:section-title id="sectitle0010">Summary</ce:section-title><ce:abstract-s... 展开 <![CDATA[<ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" xmlns="http://www.elsevier.com/xml/ja/dtd" id="abs0010" view="all" class="author"><ce:section-title id="sectitle0010">Summary</ce:section-title><ce:abstract-sec id="abssec0010" view="all"><ce:simple-para id="abspara0010" view="all">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 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<ce:sup loc="post">+</ce:sup>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.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" xmlns="http://www.elsevier.com/xml/ja/dtd" class="graphical" id="abs0015" view="all"><ce:section-title id="sectitle0015">Graphical Abstract</ce:section-title><ce:abstract-sec id="abssec0015" view="all"><ce:simple-para>Display Omitted</ce:simple-para></ce:abstract-sec></ce:abstract><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" xmlns="http://www.elsevier.com/xml/ja/dtd" class="author-highlights" id="abs0020" view="all"><ce:section-title id="sectitle0020">Highlights</ce:section-title><ce:abstract-sec id="abssec0020" view="all"><ce:simple-para id="abspara0020" view="all"><ce:list id="ulist0010"><ce:list-item id="u0010"><ce:label>?</ce:label><ce:para id="p0010" view="all">CYP3A4 is an arachidonic acid (AA) epoxygenase required for breast tumor formation</ce:para></ce:list-item><ce:list-item id="u0015"><ce:label>?</ce:label><ce:para id="p0015" view="all">CYP3A4 suppresses autophagy in breast cancer, in part, by inhibiting AMPK activation</ce:para></ce:list-item><ce:list-item id="u0020"><ce:label>?</ce:label><ce:para id="p0020" view="all">CYP3A4 AA epoxygenase activity promotes the mitochondrial electron transport chain</ce:para></ce:list-item><ce:list-item id="u0025"><ce:label>?</ce:label><ce:para id="p0025" view="all">Metformin inhibits breast cancer, in part, by inhibiting CYP3A4 AA epoxygenase activity</ce:para></ce:list-item></ce:list></ce:simple-para></ce:abstract-sec></ce:abstract><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" xmlns="http://www.elsevier.com/xml/ja/dtd" class="teaser" id="abs0025" view="all"><ce:abstract-sec id="abssec0025" view="all"><ce:simple-para id="abspara0025" view="all">Guo et?al. discover inhibition of CYP3A4 AA epoxygenase by biguanides, thereby demonstrating convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.</ce:simple-para></ce:abstract-sec></ce:abstract>]]> 收起