Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1867, Issue 10, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2020.118761
Keywords
XIAP; Subcellular localization; Breast cancer; Drug resistance; Prognosis
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E-26/010.001808/2016]
- L'oreal-UNESCO-ABC Para Mulheres na Ciencia (L'oreal for women in science)
- Brazilian National Cancer Institute Ministry of Health (INCA-MS)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) Produtividade [304565/2016-4]
- FAPESP [2016/21310-6, 2016/25798-3]
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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.
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