Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress

2022
journal article
article
2
dc.abstract.enBackground: Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. Methods: Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. Results: Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC3_DCX20 reacted to metformin with the Warburg effect; however, PC3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial–mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. Conclusions: Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.pl
dc.affiliationWydział Biochemii, Biofizyki i Biotechnologii : Zakład Biologii Komórkipl
dc.affiliationWydział Biochemii, Biofizyki i Biotechnologii : Zakład Biochemii Fizycznejpl
dc.affiliationWydział Lekarski : Instytut Pediatriipl
dc.affiliationSzkoła Doktorska Nauk Ścisłych i Przyrodniczychpl
dc.cm.id110566
dc.cm.idOmegaUJCM5679afa49f2644e6b6644727ed446bee
dc.cm.idOmegaUJCM5679afa49f2644e6b6644727ed446beepl
dc.contributor.authorCatapano, Jessica - 209642 pl
dc.contributor.authorLuty, Marcin - 177715 pl
dc.contributor.authorWróbel, Tomasz - 208660 pl
dc.contributor.authorPudełek, Maciej - 258123 pl
dc.contributor.authorPiwowarczyk, Katarzyna - 104208 pl
dc.contributor.authorKędracka-Krok, Sylwia - 128739 pl
dc.contributor.authorSiedlar, Maciej - 133377 pl
dc.contributor.authorMadeja, Zbigniew - 130173 pl
dc.contributor.authorCzyż, Jarosław - 127677 pl
dc.date.accession2022-12-13pl
dc.date.accessioned2022-12-14T09:31:21Z
dc.date.available2022-12-14T09:31:21Z
dc.date.issued2022pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.additionalBibliogr.pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume27pl
dc.identifier.articleid100pl
dc.identifier.doi10.1186/s11658-022-00400-1pl
dc.identifier.eissn1689-1392pl
dc.identifier.issn1425-8153pl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/304740
dc.identifier.weblinkhttps://cmbl.biomedcentral.com/articles/10.1186/s11658-022-00400-1pl
dc.languageengpl
dc.language.containerengpl
dc.pbn.affiliationDziedzina nauk medycznych i nauk o zdrowiu : nauki medyczne
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeOtwarte czasopismo
dc.subject.enmetabolic stresspl
dc.subject.endrug resistancepl
dc.subject.enprostate cancerpl
dc.subject.enmetabolic adaptationpl
dc.subject.enmetforminpl
dc.subtypeArticlepl
dc.titleAcquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stresspl
dc.title.journalCellular and Molecular Biology Letterspl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
Background: Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. Methods: Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. Results: Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC3_DCX20 reacted to metformin with the Warburg effect; however, PC3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial–mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. Conclusions: Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.
dc.affiliationpl
Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Biologii Komórki
dc.affiliationpl
Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Biochemii Fizycznej
dc.affiliationpl
Wydział Lekarski : Instytut Pediatrii
dc.affiliationpl
Szkoła Doktorska Nauk Ścisłych i Przyrodniczych
dc.cm.id
110566
dc.cm.idOmega
UJCM5679afa49f2644e6b6644727ed446bee
dc.cm.idOmegapl
UJCM5679afa49f2644e6b6644727ed446bee
dc.contributor.authorpl
Catapano, Jessica - 209642
dc.contributor.authorpl
Luty, Marcin - 177715
dc.contributor.authorpl
Wróbel, Tomasz - 208660
dc.contributor.authorpl
Pudełek, Maciej - 258123
dc.contributor.authorpl
Piwowarczyk, Katarzyna - 104208
dc.contributor.authorpl
Kędracka-Krok, Sylwia - 128739
dc.contributor.authorpl
Siedlar, Maciej - 133377
dc.contributor.authorpl
Madeja, Zbigniew - 130173
dc.contributor.authorpl
Czyż, Jarosław - 127677
dc.date.accessionpl
2022-12-13
dc.date.accessioned
2022-12-14T09:31:21Z
dc.date.available
2022-12-14T09:31:21Z
dc.date.issuedpl
2022
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.additionalpl
Bibliogr.
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
27
dc.identifier.articleidpl
100
dc.identifier.doipl
10.1186/s11658-022-00400-1
dc.identifier.eissnpl
1689-1392
dc.identifier.issnpl
1425-8153
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/304740
dc.identifier.weblinkpl
https://cmbl.biomedcentral.com/articles/10.1186/s11658-022-00400-1
dc.languagepl
eng
dc.language.containerpl
eng
dc.pbn.affiliation
Dziedzina nauk medycznych i nauk o zdrowiu : nauki medyczne
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
Otwarte czasopismo
dc.subject.enpl
metabolic stress
dc.subject.enpl
drug resistance
dc.subject.enpl
prostate cancer
dc.subject.enpl
metabolic adaptation
dc.subject.enpl
metformin
dc.subtypepl
Article
dc.titlepl
Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress
dc.title.journalpl
Cellular and Molecular Biology Letters
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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