Expression of nuclear XIAP associates with cell growth and drug resistance and confers poor prognosis in breast cancer

Author(s):Show less -

Delbue, Deborah ^[1] ; Mendonca, Bruna S. ^{[1, 2]} ; Robaina, Marcela C. ^[1] ; Lemos, Lauana G. T. ^[1] ; Lucena, I, Pedro ; Viola, Joao P. B. ^[3] ; Magalhaes, Lidia M. ^[4] ; Crocamo, Susanne ^[5] ; Oliveira, Caio A. B. ^[6] ; Teixeira, Felipe R. ^[6] ; Maia, Raquel C. ^[1] ; de Moraes, Gabriela Nestal ^[1]

Affiliation

^[1] Inst Nacl Canc INCA, Lab Hematooncol Celular & Mol, Programa Hematooncol Mol, Praca Cruz Vermelha 23, 6 Andar, BR-20230130 Rio De Janeiro, RJ - Brazil

^[2] INCA, Programa Posgrad Stricto Sensu Oncol, Rua Andre Cavalcanti 37, 5 Andar, BR-20230050 Centro, RJ - Brazil

^[3] Lucena, Pedro, I, INCA, Programa Imunol & Biol Tumoral, Rua Andre Cavalcanti 37, 5 Andar, BR-20230050 Centro, RJ - Brazil

^[4] INCA, Div Anat Patol, Rua Cordeiro Graca 156, BR-20220400 Rio De Janeiro - Brazil

^[5] Hosp Canc III, INCA, Nucleo Pesquisa Clin, Rua Visconde Santa Isabel 274, BR-20560120 Rio De Janeiro - Brazil

^[6] Univ Fed Sao Carlos, Dept Genet & Evolucao, Rodovia Washington Luis, Km 235, BR-13560300 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH; v. 1867, n. 10 OCT 2020.
• Web of Science Citations: 0

Abstract

Evasion from apoptosis is one of the hallmarks of cancer. X-linked inhibitor of apoptosis protein (XIAP) is known to modulate apoptosis by inhibiting caspases and ubiquitinating target proteins. XIAP is mainly found at the cytoplasm, but recent data link nuclear XIAP to poor prognosis in breast cancer. Here, we generated a mutant form of XIAP with a nuclear localization signal (XIAP(NLs-C-term)) and investigated the oncogenic mechanisms associated with nuclear XIAP in breast cancer. Our results show that cells overexpressing XIAP(Delta RING) (RING deletion) and XIAP(NLs-C-term) exhibited XIAP nuclear localization more abundantly than XIAP(wild-type), Remarkably, overexpression of XIAP(NLs-C-term) but not XIAP(Delta RING), conferred resistance to doxorubicin and in- creased cellular proliferative capacity. Interestingly, Survivin and c-IAP1 expression were not associated with XIAP oncogenic effects. However, NF kappa B expression and ubiquitination of K63, but not K48 chains, were increased following XIAP(NLs-C-term) overexpression, pointing to nuclear signaling transduction. Consistently, multivariate analysis revealed nuclear, but not cytoplasmic XIAP, as an independent prognostic factor in hormone receptor-negative breast cancer patients. Altogether, our findings suggest that nuclear XIAP confers poor outcome and RING-associated breast cancer growth and chemoresistance. (AU)

• FAPESP's process: 16/25798-3 - Functional consequences of rearrangements to the FBXL17 gene detected in patient samples and cancer cell lines, on the E3 ubiquitin-ligase SCF(Fbxl17) activity
• Grantee: Felipe Roberti Teixeira
• Support type: Regular Research Grants
• FAPESP's process: 16/21310-6 - Regulations mechanisms of the Wnt signalling pathway by E3 ubiquitin ligase SCF(Fbxo7)
• Grantee: Caio Almeida Batista de Oliveira
• Support type: Scholarships in Brazil - Master