Inhibition of Aurora kinase A activity enhances the antitumor response of beta-catenin blockade in human adrenocortical cancer cells

Author(s):Show less -

Maria, Andrea Gutierrez ^{[1, 2]} ; Borges, Kleiton Silva ^{[1, 3]} ; Lira, R. C. P. ^{[1, 4]} ; Thome, Carolina Hassib ^{[5, 6]} ; Berthon, Annabel ^[2] ; Drougat, Ludivine ^[2] ; Kiseljak-Vassiliades, Katja ^{[6, 7]} ; Wierman, Margaret E. ^{[6, 7]} ; Faucz, Fabio R. ^[2] ; Faca, Vitor Marcel ^[5] ; Tone, Luiz Gonzaga ^[1] ; Stratakis, Constantine A. ^{[2, 8]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, NIH, Bethesda, MD 20892 - USA

^[3] Harvard Med Sch, Dept Pediat, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 - USA

^[4] Univ Fed Triangulo Mineiro, Dept Gen Pathol, BR-38025180 Uberaba, MG - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP - Brazil

^[6] Vet Affairs Med Ctr, Res Serv, Denver, CO 80045 - USA

^[7] Univ Colorado, Sch Med, Div Endocrinol Metab & Diabet, Aurora, CO 80045 - USA

^[8] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD - USA

• Document type: Journal article
• Source: Molecular and Cellular Endocrinology; v. 528, MAY 15 2021.
• Web of Science Citations: 0

Abstract

Adrenocortical cancer (ACC) is a rare and aggressive type of endocrine tumor with high risk of recurrence and metastasis. The overall survival of patients diagnosed with ACC is low and treatment for metastatic stages remain limited to mitotane, which has low efficiency in advanced stages of the disease and is associated with high toxicity. Therefore, identification of new biological targets to improve ACC treatment is crucial. Blockade of the Wnt/beta-catenin pathway decreased adrenal steroidogenesis and increased apoptosis of NCI-H295 human ACC cells, in vitro and in a xenograft mouse model. Aurora kinases play important roles in cell division during the G1M phase and their aberrant expression is correlated with a poor prognosis in different types of tumors. Hence, we hypothesized that inhibition of aurora kinases activity combined with the beta-catenin pathway blockade would improve the impairment of ACC cell growth in vitro. We studied the combinatorial effects of AMG 900, an aurora kinase inhibitor and PNU-74654, a beta-catenin pathway blocker, on proliferation, survival and tumor progression in multiple ACC cell lines: NCI-H295, CU-ACC1 and CU-ACC2. Exposure of ACC cells to the combination of AMG 900 with PNU-74654 decreased cell proliferation and viability compared to either treatment alone. In addition, AMG 900 inhibited cell invasion and clonogenesis compared to PNU-74654, and the combination showed no greater effects. In contrast, PNU-74654 was more effective in decreasing cortisol secretion. These data suggest that inhibition of aurora kinases activity combined with blockade of the beta-catenin pathway may provide a combinatorial approach for targeting ACC tumors. (AU)

• FAPESP's process: 14/16839-2 - Study of pathways involved in Aurora kinases signaling and mechanisms of action of the inhibitor AMG 900 in adrenocortical tumor
• Grantee: Andrea Gutierrez Maria
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/23713-8 - Study of aurora kinases as potential biomarkers and its correlation with PKA dysfunction in adrenocortical tumors
• Grantee: Andrea Gutierrez Maria
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 14/20341-0 - Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies
• Grantee: Luiz Gonzaga Tone
• Support Opportunities: Research Projects - Thematic Grants