TY - JOUR
T1 - IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer
AU - De Martino, Maria Cristina
AU - van Koetsveld, Peter M.
AU - Feelders, Richard A.
AU - de Herder, Wouter W.
AU - Dogan, Fadime
AU - Janssen, Joseph A.M.J.L.
AU - Hofste op Bruinink, Davine
AU - Pivonello, Claudia
AU - Waaijers, A. Marlijn
AU - Colao, Annamaria
AU - de Krijger, Ronald R.
AU - Pivonello, Rosario
AU - Hofland, Leo J.
N1 - Funding Information:
We thank D.M. Sprij-Mooij for the expert assistance with RT-qPCR. Research involving human participants and/or animals: This study was approved by the Medical Ethics Committee of the Erasmus MC Conception and design: MCDM; PMvK; RAF; LJH. Development of methodology: MCDM; PMvK; FD; DhoB; AMW; LJH. Acquisition of data: MCDM; PMvK; FD; DhoB; CP. Analysis and interpretation of data: MCDM; PMvK; RAF; WWdH; JAMJLJ; RP; AC; RRdK; DhoB; CP; LJH. Writing, review and/or revision of the manuscript: MCDM; RAF; WWdH; JAMJLJ; RP; AC; RRdK; DhoB; CP; LJH. Administrative, technical, or material support: MCDM; PMvK; FD; AMW. Study supervision: RAF; RP; LJH. All the authors approved the current manuscript as the final version to be published.
Funding Information:
Acknowledgements We thank D.M. Sprij-Mooij for the expert assistance with RT-qPCR. Research involving human participants and/or animals: This study was approved by the Medical Ethics Committee of the Erasmus MC Author contributions Conception and design: MCDM; PMvK; RAF; LJH. Development of methodology: MCDM; PMvK; FD; DhoB; AMW; LJH. Acquisition of data: MCDM; PMvK; FD; DhoB; CP. Analysis and interpretation of data: MCDM; PMvK; RAF; WWdH; JAMJLJ; RP; AC; RRdK; DhoB; CP; LJH. Writing, review and/or revision of the manuscript: MCDM; RAF; WWdH; JAMJLJ; RP; AC; RRdK; DhoB; CP; LJH. Administrative, technical, or material support: MCDM; PMvK; FD; AMW. Study supervision: RAF; RP; LJH. All the authors approved the current manuscript as the final version to be published.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/6/15
Y1 - 2019/6/15
N2 - Purpose: The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. Methods: The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. Results: A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. Conclusions: In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.
AB - Purpose: The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. Methods: The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. Results: A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. Conclusions: In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.
KW - Adrenal
KW - Adrenocortical cancer
KW - IGF
KW - Insulin receptor
KW - Linsitinib
UR - http://www.scopus.com/inward/record.url?scp=85062772708&partnerID=8YFLogxK
U2 - 10.1007/s12020-019-01869-1
DO - 10.1007/s12020-019-01869-1
M3 - Article
C2 - 30838516
AN - SCOPUS:85062772708
SN - 1355-008X
VL - 64
SP - 673
EP - 684
JO - Endocrine
JF - Endocrine
IS - 3
ER -