Abstract
BackgroundAlthough the prognosis of chronic myeloid leukemia (CML) has dramatically improved, the pathogenesis of CML remains elusive. Studies have shown that sustained phosphorylation of AKT1 plays a crucial role in the proliferation of CML cells. Evidence indicates that in tongue cancer cells, FAM168A, also known as tongue cancer resistance-associated protein (TCRP1), can directly bind to AKT1 and regulate AKT1/NFκB signaling pathways. This study aimed to investigate the role of FAM168A in regulation of AKT1/NFκB signaling pathway and cell cycle in CML.MethodsFAM168A interference was performed, and the expression and phosphorylation of FAM168A downstream proteins were measured in K562 CML cell line. The possible roles of FAM168A in the proliferation of CML cells were investigated using in vitro cell culture, in vivo animal models and clinical specimens.ResultsWe found that the expression of FAM168A significantly increased in the peripheral blood mononuclear cells of CML patients, compared with normal healthy controls. FAM168A interference did not change AKT1 protein expression, but significantly decreased AKT1 phosphorylation, significantly increased IκB-α protein level, and significantly reduced nuclear NFκB protein level. Moreover, there was a significant increase of G2/M phase cells and Cyclin B1 level. Immunoprecipitation results showed that FAM168A interacts with breakpoint cluster region (BCR) -Abelson murine leukemia (ABL1) fusion protein and AKT1, respectively. Animal experiments confirmed that FAM168A interference prolonged the survival and reduced the tumor formation in mice inoculated with K562 cells. The results of clinical specimens showed that FAM168A expression and AKT1 phosphorylation were significantly elevated in CML patients.ConclusionThis study demonstrates that FAM168A may act as a linker protein that binds to BCR-ABL1 and AKT1, which further mediates the downstream signaling pathways in CML. Our findings demonstrate that FAM168A may be involved in the regulation of AKT1/NFκB signaling pathway and cell cycle in CML.
Highlights
The prognosis of chronic myeloid leukemia (CML) has dramatically improved, the pathogenesis of CML remains elusive
We found that the Tongue cancer resistanceassociated protein (FAM168A) mRNA and protein expressions in PBMCs of CML patients, as well as K562 cells, were significantly higher compared to healthy controls, suggesting that FAM168A may be involved in the CML development (Fig. 1)
FAM168A is involved in the regulation of AKT1/NFκB signaling pathway in K562 cells We investigated the impact of FAM168A interference on the expression of AKT1, phosphorylated-AKT1 (p-AKT1) and IκB-α
Summary
The prognosis of chronic myeloid leukemia (CML) has dramatically improved, the pathogenesis of CML remains elusive. Studies have shown that the Philadelphia chromosome produces a fusion gene, which in turn encodes the BCR-ABL1 fusion protein. Liu et al BMC Cancer (2019) 19:679 a sustained tyrosine kinase activity and it can promote phosphorylation of downstream signaling proteins such as AKT1, ERK, and STAT1 It can increase the expression of oncogene c-Myc and apoptosis suppressor gene Bcl-2, and promote cell proliferation and survival [4,5,6]. It is still unclear how BCR-ABL1 protein promotes the sustained phosphorylation of AKT1 protein
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