Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Abstract

Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for β-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC 50 s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/ cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl T315I , or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines.

Galectin-9: An anticancer molecule for gallbladder carcinoma

“…This apoptotic signaling in multiple myeloma was caspase-dependent and was induced by the activation of the MAP kinases JNK and p38 (22,29). Alternatively, Gal-9 induced apoptosis in chronic myelogenous leukemia by inducing Noxa (12). In the present study, Gal-9 increased the levels of cCK18 in NOZ cells, which are sensitive to Gal-9.…”

“…Previous findings suggested that Gal-9 suppresses the proliferation of melanoma (11) and chromic myeloid leukemia (12). Regarding the mechanism underlying Gal-9-induced cell growth inhibition in various cancers, Gal-9 induces cancer cell death via an apoptotic signaling pathway (11)(12)(13). This apoptotic signaling in multiple myeloma was caspase-dependent and was induced by the activation of the MAP kinases JNK and p38 (22,29).…”

“…Further research showed that Gal-9 induces apoptosis in T-cells and stimulates regulatory T-cell activity (5-7). Previous findings suggested that Gal-9 suppresses the proliferation of melanoma (11) and chromic myeloid leukemia (12). Regarding the mechanism underlying Gal-9-induced cell growth inhibition in various cancers, Gal-9 induces cancer cell death via an apoptotic signaling pathway (11)(12)(13).…”

“…It has become apparent that miRNA expression is associated with various cancers (16). Our previous studies reported that miRNAs lead to apoptosis as a consequence of the antitumor effect of Gal-9 in HCC and cholangiocarcinoma (11,12). Hierarchical cluster analyses were performed to clarify the alteration in the expression of miRNAs by Gal-9 treatment.…”

“…Interestingly, Gal-9 has been tested as a potential therapeutic agent for various autoimmune diseases (7) and allergic diseases (8). Furthermore, it has been reported that Gal-9 suppresses the cell proliferation and tumor growth of various human cancer types (9,10), such as melanoma (11) and chronic myelogenous leukemia (12). We have previously shown that Gal-9 suppressed the cell proliferation and tumor growth of human hepatocellular carcinoma (HCC) and cholangiocarcinoma by inducing apoptosis, and we have identified several microRNAs (miRNAs) that are associated with the antitumor effect of Gal-9 (13,14).…”