Therapeutically blocking Interleukin-11 Receptor-a enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours

Download
Author
Winship, A; Van Sinderen, M; Rainczuk, K; Dimitriadis, EDate
2017-04-04Source Title
OncotargetPublisher
IMPACT JOURNALS LLCUniversity of Melbourne Author/s
Dimitriadis, EvdokiaAffiliation
Obstetrics and GynaecologyMetadata
Show full item recordDocument Type
Journal ArticleCitations
Winship, A., Van Sinderen, M., Rainczuk, K. & Dimitriadis, E. (2017). Therapeutically blocking Interleukin-11 Receptor-a enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours. ONCOTARGET, 8 (14), pp.22716-22729. https://doi.org/10.18632/oncotarget.15187.Access Status
Open AccessAbstract
High grade type I endometrial cancers have poor prognosis. Interleukin (IL)11 is elevated in tumours and uterine lavage with increasing tumour grade in women. IL11 regulates cell cycle, invasion and migration and we recently demonstrated that IL11 receptor (R)α inhibition impaired low and moderate grade endometrial tumourigenesis in vivo. In this report, we hypothesized that micro-RNA(miR)-1 regulates IL11 and that IL11 promotes high grade endometrial tumour growth. We aimed to determine whether combination treatment using an anti-human IL11Rα blocking antibody (Ab) and doxorubicin chemotherapeutic impairs high grade tumour growth. MiR-1 was absent in human endometrial tumours versus human benign endometrium (n = 10/group). Transfection with miR-1 mimic restored miR-1 expression, down-regulated IL11 mRNA and impaired cell viability in grade 3-derived AN3CA human endometrial epithelial cancer cells. AN3CA cell proliferation was reduced in response to Ab and doxorubicin combination treatment versus Ab, IgG control, or doxorubicin alone. Subcutaneous xenograft tumours were established in female Balb/c athymic nude mice using AN3CA cells expressing IL11 and IL11Rα. Administration of recombinant human IL11 to mice (n = 4/group) activated IL11 downstream target, signal transducers and activators of transcription (STAT3) and significantly increased tumour growth (p < 0.05), suggesting that IL11 promotes high grade tumour growth. IL11Rα blocking Ab reduced STAT3 phosphorylation and combination treatment with doxorubicin resulted in a significant reduction in tumour growth (p < 0.05) compared to Ab, doxorubicin, or IgG control. Our data suggest that therapeutically targeting IL11Rα in combination with doxorubicin chemotherapy could inhibit high grade type I endometrioid cancer growth.
Export Reference in RIS Format
Endnote
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
Refworks
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References