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Treatment with HIV-...
Treatment with HIV-protease inhibitor nelfinavir identifies membrane lipid composition and fluidity as a therapeutic target in advanced multiple myeloma
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Besse, Lenka (author)
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Besse, Andrej (author)
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Stolze, Sara C. (author)
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show more...
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Sobh, Amin (author)
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Zaal, Esther A. (author)
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Ham, Alwin J.Van Der (author)
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- Ruiz, Mario, 1984 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Phuyal, Santosh (author)
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Buchler, Lorina (author)
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Sathianathan, Marc (author)
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Florea, Bogdan I. (author)
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- Borén, Jan, 1963 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Ståhlman, Marcus, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory
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Huber, Julia (author)
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Bolomsky, Arnold (author)
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Ludwig, Heinz (author)
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Hannich, J. Thomas (author)
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Loguinov, Alex (author)
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Everts, Bart (author)
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Berkers, Celia R. (author)
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- Pilon, Marc, 1966 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Farhan, Hesso (author)
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Vulpe, Christopher D. (author)
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Overkleeft, Herman S. (author)
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Driessen, Christoph (author)
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(creator_code:org_t)
- 2021
- 2021
- English.
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 81, s. 4581-4593
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Abstract
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- The HIV-protease inhibitor nelfinavir has shown broad anticancer activity in various preclinical and clinical contexts.In patients with advanced, proteasome inhibitor (PI)-refractory multiple myeloma, nelfinavir-based therapy resulted in 65% partial response or better, suggesting that this may be a highly active chemotherapeutic option in this setting.The broad anticancer mechanism of action of nelfinavir implies that it interferes with fundamental aspects of cancer cell biology.We combined proteome-wide affinity-purification of nelfinavir-interacting proteins with genome-wide CRISPR/Cas9-based screening to identify protein partners that interact with nelfinavir in an activity-dependent manner alongside candidate genetic contributors affecting nelfinavir cytotoxicity.Nelfinavir had multiple activity-specific binding partners embedded in lipid bilayers of mitochondria and the endoplasmic reticulum.Nelfinavir affected the fluidity and composition of lipid-rich membranes, disrupted mitochondrial respiration, blocked vesicular transport, and affected the function of membrane-embedded drug efflux transporter ABCB1, triggering the integrated stress response.Sensitivity to nelfinavir was dependent on ADIPOR2, which maintains membrane fluidity by promoting fatty acid desaturation and incorporation into phospholipids.Supplementation with fatty acids prevented the nelfinavir-induced effect on mitochondrial metabolism, drug-efflux transporters, and stress-response activation.Conversely, depletion of fatty acids/cholesterol pools by the FDAapproved drug ezetimibe showed a synergistic anticancer activity with nelfinavir in vitro.These results identify the modification of lipid-rich membranes by nelfinavir as a novel mechanism of action to achieve broad anticancer activity, which may be suitable for the treatment of PI-refractory multiple myeloma.
Subject headings
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Besse, Lenka
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Besse, Andrej
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Stolze, Sara C.
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Sobh, Amin
-
Zaal, Esther A.
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Ham, Alwin J.Van ...
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show more...
-
Ruiz, Mario, 198 ...
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Phuyal, Santosh
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Buchler, Lorina
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Sathianathan, Ma ...
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Florea, Bogdan I ...
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Borén, Jan, 1963
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Ståhlman, Marcus ...
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Huber, Julia
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Bolomsky, Arnold
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Ludwig, Heinz
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Hannich, J. Thom ...
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Loguinov, Alex
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Everts, Bart
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Berkers, Celia R ...
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Pilon, Marc, 196 ...
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Farhan, Hesso
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Vulpe, Christoph ...
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Overkleeft, Herm ...
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Driessen, Christ ...
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Cell Biology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Cancer Research
- By the university
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University of Gothenburg