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Inhibiting the endo...
Inhibiting the endoplasmic reticulum stress response enhances the effect of doxorubicin by altering the lipid metabolism of liver cancer cells
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- Kopsida, Maria (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Clavero, Ada Lerma (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Khaled, Jaafar (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Balgoma, David (author)
- Uppsala universitet,Analytisk farmaceutisk kemi,Univ Valladolide, Un Excelencia, Inst Biol & Genet Mol IBGM, Consejo Super Invest Cient CSIC, Valladolid, Spain.
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- Luna-Marco, Clara (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Chowdhury, Azazul Islam (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Sennefelt Nyman, Sofi (author)
- Uppsala universitet,Radiologi
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- Rorsman, Fredrik, Docent, 1960- (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Ebeling Barbier, Charlotte (author)
- Uppsala universitet,Radiologi
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- Bergsten, Peter (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Lennernäs, Hans (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Hedeland, Mikael (author)
- Uppsala universitet,Analytisk farmaceutisk kemi
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- Heindryckx, Femke (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Institutionen för medicinsk cellbiologi
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(creator_code:org_t)
- Elsevier, 2024
- 2024
- English.
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In: Molecular Metabolism. - : Elsevier. - 2212-8778. ; 79
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Abstract
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- Hepatocellular carcinoma (HCC) is characterized by a low and variable response to chemotherapeutic treatments. One contributing factor to the overall pharmacodynamics is the activation of endoplasmic reticulum (ER) stress pathways. This is a cellular stress mechanism that becomes activated when the cell's need for protein synthesis surpasses the ER's capacity to maintain accurate protein folding, and has been implicated in creating drug-resistance in several solid tumors. Objective: To identify the role of ER-stress and lipid metabolism in mediating drug response in HCC. Methods: By using a chemically-induced mouse model for HCC, we administered the ER-stress inhibitor 4m8C and/or doxorubicin (DOX) twice weekly for three weeks post-tumor initiation. Histological analyses were performed alongside comprehensive molecular biology and lipidomics assessments of isolated liver samples. In vitro models, including HCC cells, spheroids, and patient-derived liver organoids were subjected to 4m8C and/or DOX, enabling us to assess their synergistic effects on cellular viability, lipid metabolism, and oxygen consumption rate. Results: We reveal a pivotal synergy between ER-stress modulation and drug response in HCC. The inhibition of ER-stress using 4m8C not only enhances the cytotoxic effect of DOX, but also significantly reduces cellular lipid metabolism. This intricate interplay culminates in the deprivation of energy reserves essential for the sustenance of tumor cells. Conclusions: This study elucidates the interplay between lipid metabolism and ER-stress modulation in enhancing doxorubicin efficacy in HCC. This novel approach not only deepens our understanding of the disease, but also uncovers a promising avenue for therapeutic innovation. The long-term impact of our study could open the possibility of ER-stress inhibitors and/or lipase inhibitors as adjuvant treatments for HCC-patients. (c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Lipidomics
- Hepatocellular carcinoma
- Endoplasmic reticulum stress
- Chemotherapy
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Kopsida, Maria
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Clavero, Ada Ler ...
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Khaled, Jaafar
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Balgoma, David
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Luna-Marco, Clar ...
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Chowdhury, Azazu ...
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Sennefelt Nyman, ...
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Rorsman, Fredrik ...
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Ebeling Barbier, ...
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Bergsten, Peter
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Lennernäs, Hans
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Hedeland, Mikael
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Heindryckx, Femk ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Molecular Metabo ...
- By the university
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Uppsala University