dc.contributor.author
Dahlmann, Mathias
dc.contributor.author
Werner, Rebecca
dc.contributor.author
Kortüm, Benedikt
dc.contributor.author
Kobelt, Dennis
dc.contributor.author
Walther, Wolfgang
dc.contributor.author
Stein, Ulrike
dc.date.accessioned
2020-07-03T12:52:36Z
dc.date.available
2020-07-03T12:52:36Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/27420
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-27176
dc.description.abstract
Treatment failure of solid cancers, represented by the development of drug resistance in the primary tumor or later outgrowth of drug resistant metastases, is the major cause of death for cancer patients. It represents an urgent clinical need for predictive biomarkers which indicate the success or failure of standard treatment regimens. Besides treatment prediction, interfering with cellular processes associated with drug resistance might improve treatment response by applying combination therapies. Metastasis-associated in colon cancer (MACC) 1 was identified in our group as a prognostic biomarker in human colorectal cancer, and has been established as key player, prognostic, and predictive biomarker for tumor progression and metastasis in a variety of solid cancers. Besides increased cell proliferation and motility, subsequently contributing to growth and metastatic spread of the primary tumor, MACC1 has also been shown to dysregulate apoptosis and is contributing to treatment resistance. Here we report the MACC1 dependent treatment resistance of colorectal cancer (CRC) cells to standard therapeutics like doxorubicin by upregulating ATP-binding cassette subfamily B member 1 (ABCB1) protein. Overexpression of MACC1 in CRC cells increased both its presence on the ABCB1 promoter and its transcriptional activity, resulting in elevated ABCB1 expression and thus treatment resistance to standard therapeutics. In contrast, depleting MACC1 increased intracellular drug concentrations, leading to better treatment response. We already identified the first MACC1 transcriptional inhibitors, such as lovastatin, by high-throughput screening of clinically approved small molecule drugs. These compounds inhibited cell motility in vitro but also restricted metastasis development in xenograft mouse models by reducing MACC1 expression. Here we report, that treating high MACC1 expressing CRC cells with a combination of statins and standard therapeutics increased the rate of cytotoxicity and resulted in higher treatment response.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
colorectal cancer
en
dc.subject
multi-drug resistance
en
dc.subject
combination therapy
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Restoring Treatment Response in Colorectal Cancer Cells by Targeting MACC1-Dependent ABCB1 Expression in Combination Therapy
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
599
dcterms.bibliographicCitation.doi
10.3389/fonc.2020.00599
dcterms.bibliographicCitation.journaltitle
Frontiers in Oncology
dcterms.bibliographicCitation.originalpublishername
Frontiers Media S.A.
dcterms.bibliographicCitation.volume
10
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.isSupplementedBy.url
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70458
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
32391276
dcterms.isPartOf.eissn
2234-943X