The antiapoptotic protein Api5 and its partner, high molecular weight FGF2, are up-regulated in B cell chronic lymphoid leukemia

Abstract

The apoptosis inhibitor-5 [Api5; antiapoptosis clone 11 (AAC-11); fibroblast growth factor-2 (FGF2)-interacting factor (FIF)] is a 504-aa nuclear protein frequently up-regulated in tumor cells. Several studies have shown potent antiapoptotic action of Api5, which appears to be, at least in part, mediated via suppression of apoptosis depending on the E2F family of transcription factors [1][2][3][4].Human FGF2 is a prototypic member of the FGF family of growth factors and exists in several variants generated by alternative translation of a single transcript. The smallest variant, 18 kDa FGF2, is released from cells and acts through binding and activation of cell-surface FGF-receptor tyrosine kinases. In contrast, the high molecular weight (HMW) FGF2 variants (22, 22.5, and 24 kDa) localize predominantly to the nucleus and have an intracrine, FGF receptor-independent mode of action [5]. It is interesting that HMW but not 18 kDa FGF2 interacts with Api5 in mammalian cells [3]. Similar to Api5, HMW FGF2 has a prosurvival action in various experimental models [6], although it is unknown to what extent HMW FGF2 and Api5 depend functionally on each other.In B cell chronic lymphoid leukemia (B-CLL), FGF2 is up-regulated with an 18-kDa FGF2 peripheral blood concentration significantly exceeding control levels in the majority of patients with advanced disease [7]. This deregulation also involves HMW FGF2, which is overexpressed in B-CLL cells [8]. As Api5 represents the binding partner of HMW FGF2 [3], we asked whether Api5 is also up-regulated in B-CLL. We compared the expression of Api5 and HMW FGF2 in PB-MCs obtained from eight B-CLL patients and five control individuals. Figure 1A shows up-regulation of 55 kDa (full-length) Api5 and HMW FGF2 in the majority of B-CLL patients when compared with control samples. In addition to the full-length Api5, a 25-kDa truncated variant of Api5, generated by alternative translation [1], was found in some samples.The up-regulation of full-length Api5 in B-CLL (Fig. 1A) might be specific to the leukemic clones or simply represent B cell enrichment in the B-CLL PBMCs compared with control PBMCs. We therefore determined the levels of Api5 and FGF2 in PBMCs enriched for B cells via negative selection, i.e., removal of T cells, NK cells, and monocytes using magnetic bead separation. Compared with controls, there was a clear up-regulation of full-length Api5 and HMW FGF2 in the B cell-enriched PBMCs of all five B-CLL individuals (Fig. 1B). Similar results were obtained with CD19ϩ B cells purified from PBMCs via magnetic bead separation, thus confirming that B-CLL leukemic clones have up-regulated full-length Api5 and HMW FGF2 (Fig. 1C). Considering the nature of the defect leading to B-CLL, i.e., decreased apoptosis of mature B cells, Api5 and HMW FGF2 may contribute to the pathology of B-CLL.

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

“…Recently, few studies have addressed the API5 mechanism other than its anti-apoptotic effects [14, 15, 20]. The putative oncogenic role of API5 was suggested by Kim and colleagues in cervical cancer cell lines [20].…”

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

“…With the analysis of downregulated proteins, it was found that exposure to 7KC can modify levels of API5 in Lucena cells. This anti-apoptotic protein has been described as overexpressed in many cancer cells [49,50], in patients with chronic lymphocytic leukemia [51] and has also been associated with worse prognosis in non-small cell lung cancer patients [50]. One of the mechanism that could be involved is the relationship between API5 and transcription factor E2F1 [52], which promotes the transcriptional regulation of several genes, such as cyclin E, cyclin A and Cdk2, favoring the G1-S cell cycle progression but also related to induction of apoptosis following DNA damage [52].…”

Fibroblast Growth Factor-2 Signaling in Neurogenesis and Neurodegeneration

“…Interestingly, HMW FGF2 also binds to anti-apoptotic molecules Api5 and SMN and potentiates cell survival, suggesting further functional diversity as a neurotrophic factor (See Fig. 1B)[30, 31]. …”