Urokinase-type Plasminogen Activator Is a Therapeutic Target for Overcoming Sorafenib Resistance in Hepatoma Cells.

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Tytuł:: Urokinase-type Plasminogen Activator Is a Therapeutic Target for Overcoming Sorafenib Resistance in Hepatoma Cells.
Autorzy:: Osawa M; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Matsuda Y; Department of Medical Technology, Niigata University Graduate School of Health Sciences, Niigata, Japan; .
Kinoshita Y; Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Wakai T; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Źródło:: Anticancer research [Anticancer Res] 2021 Feb; Vol. 41 (2), pp. 645-660.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: Attiki, Greece : International Institute of Anticancer Research
Original Publication: Athens, Greece : Potamitis Press
MeSH Terms:: Drug Resistance, Neoplasm*/drug effects
Antineoplastic Agents/*pharmacology
Carcinoma, Hepatocellular/*drug therapy
Liver Neoplasms/*drug therapy
Membrane Proteins/*metabolism
Protein Kinase Inhibitors/*pharmacology
Sorafenib/*pharmacology
Amiloride/pharmacology ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/enzymology ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/enzymology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Male ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/genetics ; Mice, Inbred BALB C ; Mice, Nude ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Xenograft Model Antitumor Assays ; Mice
Contributed Indexing:: Keywords: Sorafenib; drug resistance; hepatocellular carcinoma; urokinase-type plasminogen activator
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (Membrane Proteins)
0 (PLAU protein, human)
0 (Protein Kinase Inhibitors)
0 (RNA, Small Interfering)
7DZO8EB0Z3 (Amiloride)
9ZOQ3TZI87 (Sorafenib)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
Entry Date(s):: Date Created: 20210131 Date Completed: 20210208 Latest Revision: 20240226
Update Code:: 20240226
DOI:: 10.21873/anticanres.14816
PMID:: 33517269
: Czasopismo naukowe

Background/aim: Sorafenib is a multikinase inhibitor approved as a first-line therapy for hepatocellular carcinoma. This study examined the sorafenib resistance mechanism.
Materials and Methods: Hepatoma HepG2 cells were exposed to sorafenib, and the biological activity of the conditioned media was analyzed using cell proliferation/apoptosis assays, multiplex immunoassays, ELISA, and western blot analyses. The effect of urokinase-type plasminogen activator (uPA) inhibitors or siRNA-mediated gene silencing was examined in culture experiments and a mouse xenograft tumor model.
Results: Sorafenib increased uPA secretion, which was abrogated by an Akt inhibitor. The growth-inhibitory effect of sorafenib was significantly enhanced by the uPA inhibitors UK122 and amiloride. Sorafenib-induced apoptosis was increased 2.4-fold in uPA siRNA-transduced cells (p<0.05). Combined therapy with sorafenib and amiloride significantly decreased tumor volumes [mean volume: 759 mm 3 (sorafenib) vs. 283 mm 3 (sorafenib plus amiloride), p<0.05].
Conclusion: uPA may play a critical role in sorafenib resistance.
(Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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