Everolimus combined with 5-aza-2-deoxycytidine generated potent anti-tumor effects on ovarian clear cell cancer stem-like/spheroid cells by inhibiting the COL6A3-AKT-mTOR pathway.
Am J Cancer Res
; 12(4): 1686-1706, 2022.
Article
in En
| MEDLINE
| ID: mdl-35530273
ABSTRACT
Ovarian clear cell cancer stem-like/spheroid cells (OCCCSCs) were associated with recurrence, metastasis, and chemoresistance in ovarian clear cell carcinoma (OCCC). We evaluated the anti-tumor effects of 5-aza-2-deoxycytidine (5-aza-dC) combined with everolimus (RAD001) on human OCCC. We investigated parental OCCCSCs and paclitaxel-resistant cell lines derived from OCCCSCs in vitro and in vivo. A Western blot analysis showed that the 5-aza-dC and RAD001 combination therapy was associated with the COL6A3-AKT-mTOR pathway. The OCCCSCs expressed high levels of stemness markers CD117, ALDH1, NANOG, OCT4, and CD133. The 5-aza-dC and RAD001 combination inhibited proliferation and survival with up to 100-fold more potency in OCCCSCs compared to OCCC cells. This combination showed significant anti-tumor activity; it preferentially diminished OCCCSC stemness levels and spheroid numbers in vitro. Limiting dilution assays showed that OCCCSCs possessed tumor-initiating capacity. The 5-aza-dC and RAD001 combination significantly enhanced the inhibition of tumor growth compared to the 5-aza-dC or RAD001 alone. OCCCSCs showed higher expression levels of COL6A3, phospho-AKT, phospho-mTOR, and phospho-Rictor compared to OCCCs. Silencing COL6A3 or abolishing the phospho-AKT-mTOR-Rictor pathway with 5-aza-dC and RAD001 treatment further enhanced OCCCSC apoptosis and reduced OCCCSC stemness. In conclusion, 5-aza-dC combined with RAD001 effectively controlled OCCC and OCCCSC growth by inhibiting the COL6A3-AKT-mTOR pathway.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Am J Cancer Res
Year:
2022
Document type:
Article
Affiliation country:
Taiwán