Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer

Abstract

BackgroundThe apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer.MethodsAPI5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues.ResultsAPI5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.ConclusionsAPI5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-545) contains supplementary material, which is available to authorized users.

Apoptosis inhibitor 5 is an endogenous inhibitor of caspase‐2

“…We confirmed the presence of API5 in active caspase-2-containing complexes by immunoblots ( Fig 1B). As shown before [14,19], API5 antibodies detect a double band in HeLa cells recognizing both the 55-and 57-kDa isoforms ( Fig 1B). Gel filtration analysis revealed that API5 and caspase-2 are shifting towards high molecular weight fractions in PFT-treated cells ( Fig 1C).…”

“…API5 also inhibits E2F1‐dependent apoptosis in a transcription‐independent manner . Recent studies revealed that API5 is highly expressed in various cancers and associated with poor prognosis especially in NSCLCs and cervical cancer; however, the molecular mechanisms behind API5‐mediated cell survival remains poorly understood . Here, we reveal that API5 directly binds to the CARD domain of caspase‐2 and prevents its dimerization and activation.…”

Identifying suitable reference genes for gene expression analysis in developing skeletal muscle in pigs

“…The API5 protein suppresses apoptosis induced by the transcription factor E2F1, and interacts with and negatively regulates Acinus, a nuclear factor involved in apoptotic DNA fragmentation. The API5 gene is involved in many human diseases including diabetes and cancers (Cho et al, 2014; Noh et al, 2014; Peng et al, 2015; Ramdas et al, 2011). However, API5 has not been reported to be involved in skeletal muscle development.…”

Common variants in or near ZNRF1, COLEC12, SCYL1BP1 and API5 are associated with diabetic retinopathy in Chinese patients with type 2 diabetes

“…SCYL1BP1 encodes SCY1-like 1-binding protein 1, a regulator of the p53 pathway with tumour-suppressive function [30][31][32]. API5 encodes the protein apoptosis inhibitor 5, which is reported to be a suppressor of apoptosis and to play a key role in tumour progression [33,34]. However, the relationships of these SNPs and other genes are largely unknown.…”