title: Therapeutically blocking Interleukin-11 Receptor-α enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours.
abstract: 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.
authors.affiliation: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, 3168, VIC, Australia.|Department of Molecular and Translational Medicine, Monash University, Clayton, 3800, VIC, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Winship
authors.affiliation: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, 3168, VIC, Australia.|Department of Molecular and Translational Medicine, Monash University, Clayton, 3800, VIC, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Van Sinderen
authors.affiliation: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, 3168, VIC, Australia.|Department of Molecular and Translational Medicine, Monash University, Clayton, 3800, VIC, Australia.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Rainczuk
authors.affiliation: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, 3168, VIC, Australia.|Department of Molecular and Translational Medicine, Monash University, Clayton, 3800, VIC, Australia.|Department of Anatomy and Developmental Biology, Monash University, Clayton, 3800, VIC, Australia.
authors.forename: Evdokia
authors.initials: E
authors.lastname: Dimitriadis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053703:Interleukin-11 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D060787:Neoplasm Grading; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; C508428:IL11RA protein, human; D053703:Interleukin-11 Receptor alpha Subunit; D004317:Doxorubicin
keywords: chemotherapy; cytokine; endometrioid