Semaphorin 4D is a potential biomarker in pediatric leukemia and promotes leukemogenesis by activating PI3K/AKT and ERK signaling pathways

Abstract

Semaphorin 4D (Sema4D) is highly expressed in a variety of tumors and is associated with high invasion, poor prognosis and poor therapeutic response. However, the expression and role of Sema4D in leukemia remains unclear. The present study investigated the expression of Sema4D in pediatric leukemia and its effects in leukemia cells. The results demonstrated that Sema4D protein was highly expressed in peripheral blood mononuclear cells of patients with pediatric leukemia, and high levels of soluble Sema4D were also observed in the plasma of these patients. Sema4D knockdown induced cell cycle arrest in G 0 /G 1 phase, inhibited proliferation and promoted apoptosis in BALL-1 cells, while Sema4D overexpression exhibited the opposite effect. In Jurkat cells, Sema4D knockdown inhibited proliferation and promoted apoptosis, while Sema4D overexpression decreased the abundance of the cells in the G 0 /G 1 phase of the cell cycle and promoted proliferation. Sema4D overexpression also increased the migratory capacity of Jurkat cells and the invasive capacity of BALL-1 cells. The phosphorylation level of PI3K was decreased in both Sema4D knocked-down Jurkat and BALL-1 cells, and the phosphorylation level of ERK was decreased in Sema4D knocked-down BALL-1 cells. The phosphorylation levels of PI3K, ERK and AKT were elevated in patients with pediatric leukemia, and were correlated to the increased Sema4D expression. Sema4D overexpression was associated with a shorter overall survival in patients with acute myeloid leukemia. Overall, the results of the present study indicated that Sema4D serves an important role in leukemia development by activating PI3K/AKT and ERK signaling, and it may be used as a potential target for the diagnosis and treatment of leukemia.

Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

“…Cur also exhibits an antitumor effect as an inhibitor of the transcription factor signal transducer and activator of transcription 3 (STAT3) in various tumors [ 18 , 19 , 20 , 21 ], and STAT3 is reported to upregulate the expression of NNMT in CRC [ 22 ]. In addition, it has been reported that Cur potentiates the effect of many chemotherapy drugs, including 5-FU [ 18 , 23 , 24 ]. It has been observed that, regardless of the drug that it is combined with, Cur always results in an enhanced effect with reduced dose and side effects [ 23 ].…”

The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses

“…This is a well-known substrate of ERK1, and is deacetylated by HDAC6, which promotes ERK1 activation and prevents cancer cell apoptosis [ 117 ]. It has been shown that an inhibition of HDAC1 and HDAC6 downregulated the expression of phospho-ERK1 in human head and neck squamous cell carcinoma cells [ 118 ].…”

Biological Activity of Naturally Derived Naphthyridines

“…Recent studies confirmed the antineoplasm effect of matrine on MCF-7 breast cancer and A549 non-small cell lung cancer cell lines by inhibiting AKT/mTOR axis [ 38 , 39 ]. Additionally, it reduced tumor growth of ovarian cancer cells in vivo by inducing the expression of ERK and JNK (c-Jun N-terminal kinase) pathways [ 40 ]. Matrine 30 also exerted a significant effect in drug-resistant tumors by inducing apoptosis and inhibiting efflux-pump activity [ 41 , 42 ].…”

“…They were documented to induce apoptosis in cancer cells in both p53-dependent and p53-independent manner [ 23 , 25 , 148 , 167 ]. Moreover, the compounds interfere with procytotoxic signaling pathways, i.a., AKT/mTOR, ERK, JNK, WNT [ 38 , 39 , 40 , 62 ]. Antineoplasm properties against drug-resistant tumors could be elucidated by inhibiting efflux-pumps activity, however, this topic requires further study [ 41 , 42 ].…”