E2F1-directed activation of Bcl-2 is correlated with lactoferrin-induced apoptosis in Jurkat leukemia T lymphocytes

Abstract

Lactoferrin (Lf) has been shown to control the proliferation of a variety of mammalian cells. Recently, we reported that human Lf induces apoptosis via a c-Jun N-terminal kinases (JNK)-associated Bcl-2 pathway that stimulates programmed cell death. In order to gain insight into the mechanism underlying Lf-triggered apoptotic features, we attempted to determine the mechanisms whereby the Lf-induced Bcl-2 family proteins exert their pro- or anti-apoptotic effects in Jurkat leukemia T lymphocytes. Treatment of the cells with high concentrations of Lf resulted in a significant reduction in in vitro growth and cell viability. As the levels of Lf increased, greater quantities of CDK6 and hyper-phosphorylated retinoblastoma protein were produced, resulting in the induction of E2F1-dependent apoptosis. Simultaneously, PARP and caspases were efficiently cleaved during Lf-induced apoptosis. The E2F1-induced apoptotic process occurred preferentially in p53-deficient Jurkat leukemia cells. Therefore, we attempted to determine whether E2F1-regulated Bcl-2 family proteins involved in the apoptotic process were relevant to Lf-induced apoptosis. We found that Lf increased the interaction of Bcl-2 with the pro-apoptotic protein Bad, whereas the total protein levels did not change significantly. Our results, collectively, suggest that Lf exploits the control mechanism of E2F1-regulated target genes or Bcl-2 family gene networks involved in the apoptotic process in Jurkat human leukemia T lymphocytes.

Lactoferrin inhibits the inflammatory and angiogenic activation of bovine aortic endothelial cells

“…The anti-proliferative activity of Lf in BAECs might be the result, at least in part, of the inhibition of DNA synthesis rather than cytotoxicity. Indeed, it has been reported that Lf inhibits cancer cell growth by inducing a growth arrest [37,38] and apoptosis [39,40]. We also found that Lf induced apoptosis in BAECs (data not shown).…”

Lactoferrin’s Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action

“…By contrast, upon treatment with a JNK inhibitor, hLf challenging no longer induced any apoptotic process in the same cell line [152]. A deeper analysis of the Lf-induced Bcl-2-dependent apoptotic signaling showed that hLf reduces the formation of the Rb/E2F1 complex by inducing the phosphorylation of Rb, thus promoting the release of E2F1 transcription factor, a downstream regulator for cell proliferation and apoptosis via activation of its target genes [153].…”

Inhibition of breast cancer xenografts in a mouse model and the induction of apoptosis in multiple breast cancer cell lines by lactoferricin B peptide

“…LTX‐315, an oncolytic peptide derived from LfcinB, was shown to exert an additive effect when used along with chemotherapy as a combination therapy against triple‐negative breast cancers in a mouse model 50 . It was also able to modulate immune response and reprogram the tumour microenvironment, and is being evaluated in clinical trials 51 …”