TY - JOUR
T1 - Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness
AU - Karvonen, Hanna
AU - Arjama, Mariliina
AU - Kaleva, Laura
AU - Niininen, Wilhelmiina
AU - Barker, Harlan
AU - Koivisto-Korander, Riitta
AU - Tapper, Johanna
AU - Pakarinen, Päivi
AU - Lassus, Heini
AU - Loukovaara, Mikko
AU - Bützow, Ralf
AU - Kallioniemi, Olli
AU - Murumägi, Astrid
AU - Ungureanu, Daniela
N1 - Funding Information:
We thank the patients for donating their samples to our research and the staff of High Throughput Biomedicine and Sequencing Laboratory Units from FIMM, University of Helsinki. We acknowledge the Tampere facility of Virus Production and Tampere facility of Flow Cytometry for their services. This research was funded by the Academy of Finland (grants 275525, 284663, Finnish Center of Excellence Program 312041), Cancer Society of Finland, Sigrid Jusélius Foundation, and Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital (9V068) to D.U.; Emil Aaltonen Foundation and Finnish Cultural Foundation – Pirkanmaa Regional Fund to H.K.; Academy of Finland (grants 278741 and 271845) to O.K.; EVO (TYH2016204) to R.B.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.
AB - Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.
U2 - 10.1038/s41419-020-03009-4
DO - 10.1038/s41419-020-03009-4
M3 - Article
C2 - 32989221
AN - SCOPUS:85091637053
SN - 2041-4889
VL - 11
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 9
M1 - 790
ER -
