http://www.cnr.it/ontology/cnr/individuo/prodotto/ID274458
CISPLATINUM SENSITIVITY OF BRCA1-MUTATED HCC1937 BREAST CANCER CELLS IS LINKED TO IMPAIRMENT OF NOTCH SIGNALING AND IS INCREASED BY GAMMA-SECRETASE INHIBITORS (Comunicazione a convegno)
- Type
- Label
- CISPLATINUM SENSITIVITY OF BRCA1-MUTATED HCC1937 BREAST CANCER CELLS IS LINKED TO IMPAIRMENT OF NOTCH SIGNALING AND IS INCREASED BY GAMMA-SECRETASE INHIBITORS (Comunicazione a convegno) (literal)
- Anno
- 2010-01-01T00:00:00+01:00 (literal)
- Alternative label
Monica Ventura (1,2,4), Maria Teresa Di Martino (1,2,4), Mariamena Arbitrio (3), Pierfrancesco
Tassone (2,4) and Pierosandro Tagliaferri (1,4) (2010)
CISPLATINUM SENSITIVITY OF BRCA1-MUTATED HCC1937 BREAST CANCER CELLS IS LINKED TO IMPAIRMENT OF NOTCH SIGNALING AND IS INCREASED BY GAMMA-SECRETASE INHIBITORS
in TUMORI EREDITARI: dalla biologia molecolare al tratt amento, Modena, 18 - 19 novembre
(literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Monica Ventura (1,2,4), Maria Teresa Di Martino (1,2,4), Mariamena Arbitrio (3), Pierfrancesco
Tassone (2,4) and Pierosandro Tagliaferri (1,4) (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- 1Medical Oncology Unit and
2 Referral Center for Innovative Treatments in Medical Oncology, \"Campus
Salvatore Venuta\", \"Magna Graecia\" University and \"Tommaso Campanella\" Cancer Center, CZ
3Insti tute of Neurological Science-Nati onal Council of Research - UOS of Pharmacology - Catanzaro
4Department of Experimental and Clinical Medicine and Magna Graecia University Catanzaro (literal)
- Titolo
- CISPLATINUM SENSITIVITY OF BRCA1-MUTATED HCC1937 BREAST CANCER CELLS IS LINKED TO IMPAIRMENT OF NOTCH SIGNALING AND IS INCREASED BY GAMMA-SECRETASE INHIBITORS (literal)
- Abstract
- Obietti vo: BRCA1 plays a criti cal role in DNA-damage repair mechanisms elicited
by cell exposure to anti -tumor agents. HCC1937 is a BRCA1-defecti ve breast
cancer cell line which discloses higher sensiti vity to cisplati num (CDDP) as
compared to its derivati ve clone, HCC1937/wtBRCA1, generated in our laboratory
by full-lenght BRCA1 cDNA transfecti on. To identi fy the molecular bases
of BRCA1-related diff erenti al sensiti vity to CDDP, we analyzed the whole
gene expression profi le of HCC1937 and HCC1937/wtBRCA1 cells following in
vitro exposure to CDDP;with this experimental approach, we identi fi ed CDDPinduced
trascripti onal changes involving the Notch pathway. Preclinical evidence
suggests that combinati on strategies with plati num compounds and Notch
inhibitors may exert anti -tumor eff ects. At this aim, we evaluated in vitro anti -
proliferati ve eff ect of a pan-Notch inhibitor, ?-secretase inhibitor XII(GSI-XII) in
HCC1937 and HCC1937/wtBRCA1, alone or in combinati on with CDDP, to assess
its anti tumor acti vity in this specifi c setti ng.
Materiali e metodi: RNA was isolated from HCC1937 and HCC1937/wtBRCA1
cell lines exposed to CDDP at IC50 doses of 30 and 70?M respecti vely, for
3,12 and 24 hours. Gene expression profi ling was performed by Array 1. 0ST
(Aff ymetrix). Array data were analyzed using Gene Expression Console and
Ingenuity®Pathway Analysis(IPA). Western Blotti ng was performed in both cell
lines aft er exposure to CDDP using Notch3 M20 sc-7424 goat polyclonal IgG.
Cell proliferati on was analyzed by MTT assay on both cell lines in presence of
increasing concentrati on of CDDP, GSI-XII and combinati on of both compounds.
Risultati : By cDNA microarray whole gene expression profi le and IPA, we demonstrated
a diff erenti al modulati on of Notch signaling aft er CDDP exposure in
HCC1937 cell line as compared to HCC1937/wtBRCA1,with strong down-regulati
on of Notch1, 2 and 3 expression in HCC1937 together with other genes involved
in the Notch pathway. We demonstrated a signifi cant reducti on of Notch3
protein's expression following CDDP exposure at the IC50 dose for 12,18 and 24
hours in HCC1937 as compared to HCC1937/wtBRCA1 consistently with gene
expression results. Finally, we observed a ti me- and dose-dependent decrease
of cell growth of HCC1937 following GSI-XII exposure as compared to HCC1937/
wtBRCA1, with an IC50 between 20 and 25 ?M. Conversely, HCC1937/wtBRCA1
where highly resistant to the drug. The combinati on of 10 ?M of GSI-XII plus
CDDP at diff erent concentrati ons produced a signifi cant sinergisti c eff ect at 48
hours in HCC1937, which did not occurred in HCC1937/wtBRCA1.
Conclusioni: Our fi ndings suggest that the high sensiti vity of BRCA1-defecti ve
cells to CDDP exposure may be related not only to depression of the DNAdamage
repair machinery but also to down-modulati on of the Notch survival
pathway. GSIs deserve investi gati on as a novel therapeuti c tool in the specifi c
setti ng of BRCA1 defecti ve tumors (Supported by Italian Ministry of Educati on). (literal)
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