Abstract
Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identification of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efficacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.
Highlights
Despite significant improvements in treatment outcome in recent years [1, 2], chronic lymphocytic leukemia (CLL) – the most common leukemia in the Western world – remains incurable [3, 4]
Based on previous data showing that PI3K-mediated signals are required for survival of Chronic lymphocytic leukemia (CLL) cells in vitro [11, 13, 23], and that CK2 positively regulates PI3K pathway in CLL [9,10,11], we started by evaluating the impact of CIGB300 on the interplay between CK2 and PI3K signaling
We confirmed that the peptide efficiently prevented phosphorylation of the direct CK2 target residue S129 on Akt/PKB [24] in the MO1043 CLL cell line (Figure 1A) and in primary CLL cells (Figure 1B)
Summary
Despite significant improvements in treatment outcome in recent years [1, 2], chronic lymphocytic leukemia (CLL) – the most common leukemia in the Western world – remains incurable [3, 4]. A significant fraction of patients does not tolerate the aggressive protocols that may prolong overall survival [5]. We and others have shown that leukemia cells from CLL patients display higher CK2 expression and activity than normal B cells, leading to inhibition of PTEN and activation of PI3K signaling pathway [9, 10], which is required for CLL cell survival [11,12,13].
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