Abstract
XPO1 (exportin1) mediates nuclear export of proteins and RNAs and is frequently overexpressed in cancers. In this study, we show that the orally bioavailable XPO1 inhibitor KPT-330 reduced Mcl-1 protein level, by which it synergized with Bcl-xL inhibitor A-1331852 to induce apoptosis in cancer cells. KPT-330/A-1331852 combination disrupted bindings of Mcl-1 and Bcl-xL to Bax, Bak, and/or Bim, elicited mitochondrial outer membrane permeabilization, and triggered apoptosis. KPT-330 generally mitigated mRNA expression and protein synthesis rather than mRNA nuclear export or protein stability of Mcl-1. KPT-330 inhibited mTORC1/4E-BP1 and Mnk1/eIF4E axes, which disrupted the eIF4F translation initiation complex but was dispensable for Mcl-1 reduction and KPT-330/A-1331852 combination-induced apoptosis. Mature rRNAs are integral components of the ribosome that determines protein synthesis ability. KPT-330 impeded nucleolar rRNA processing and reduced total levels of multiple mature rRNAs. Reconstitution of XPO1 by expressing degradation-resistant C528S mutant retained rRNA amount, Mcl-1 expression, and Bcl-xL inhibitor resistance upon KPT-330 treatment. KPT-330/A-1331852 combination suppressed growth and enhanced apoptosis of non-small cell lung cancer xenografts. Therefore, we clarify the reason of apoptosis resistance of cancer cells to XPO1 inhibition and develop a potential strategy for treating solid tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Benzothiazoles / pharmacology*
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Benzothiazoles / therapeutic use
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Down-Regulation / drug effects
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Drug Synergism
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Eukaryotic Initiation Factor-4F / metabolism
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Exportin 1 Protein
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Humans
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Hydrazines / pharmacology*
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Hydrazines / therapeutic use
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Isoquinolines / pharmacology*
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Isoquinolines / therapeutic use
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Karyopherins / antagonists & inhibitors
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Karyopherins / genetics
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Karyopherins / metabolism
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Male
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Mechanistic Target of Rapamycin Complex 1 / metabolism
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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RNA, Ribosomal / metabolism*
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Triazoles / pharmacology*
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Triazoles / therapeutic use
Substances
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A-1331852
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Antineoplastic Agents
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Benzothiazoles
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Eukaryotic Initiation Factor-4F
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Hydrazines
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Isoquinolines
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Karyopherins
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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RNA, Ribosomal
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Receptors, Cytoplasmic and Nuclear
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Triazoles
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selinexor
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Mechanistic Target of Rapamycin Complex 1