{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T01:39:20Z","timestamp":1788745160280,"version":"build-2803163510"},"reference-count":122,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T00:00:00Z","timestamp":1665273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Sharjah","award":["2201110155"],"award-info":[{"award-number":["2201110155"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, wherein sorafenib, a multiple target tyrosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) database was utilized through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0\/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide metabolic pathways, energy production pathways and other pathways related to cancer aggressiveness, such as migration, proliferation and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells\u2019 survival, growth, and proliferation. Collectively, the results identified potential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.<\/jats:p>","DOI":"10.3390\/ijms231911975","type":"journal-article","created":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T20:49:31Z","timestamp":1665348571000},"page":"11975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Multi-Omics Analysis Revealed a Significant Alteration of Critical Metabolic Pathways Due to Sorafenib-Resistance in Hep3B Cell Lines"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5488-8680","authenticated-orcid":false,"given":"Kholoud Y. I.","family":"Abushawish","sequence":"first","affiliation":[{"name":"College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-615X","authenticated-orcid":false,"given":"Sameh S. M.","family":"Soliman","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander D.","family":"Giddey","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza M.","family":"Al-Hroub","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muath","family":"Mousa","sequence":"additional","affiliation":[{"name":"Research Institute of Science and Engineering, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karem H.","family":"Alzoubi","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1580-2589","authenticated-orcid":false,"given":"Waseem","family":"El-Huneidi","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5972-0681","authenticated-orcid":false,"given":"Eman","family":"Abu-Gharbieh","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4670-8149","authenticated-orcid":false,"given":"Hany A.","family":"Omar","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Elgendy","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1315-0609","authenticated-orcid":false,"given":"Yasser","family":"Bustanji","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson C.","family":"Soares","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0169-7538","authenticated-orcid":false,"given":"Mohammad H.","family":"Semreen","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e5904","DOI":"10.1097\/MD.0000000000005904","article-title":"Mortality Assessment of Patients with Hepatocellular Carcinoma According to Underlying Disease and Treatment Modalities","volume":"96","author":"Golabi","year":"2017","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/ijc.33588","article-title":"Cancer Statistics for the Year 2020: An Overview","volume":"149","author":"Ferlay","year":"2021","journal-title":"Int. J. 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