Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

Abstract

ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Galectins are a family of animal lectins that function both extracellularly (by interacting with cell surface and extracellular matrix glycoproteins and glycolipids) and intracellularly (by interacting with cytoplasmic and nuclear proteins) to modulate signaling pathways. We found that protease-resistant galectin-9 by modification of its linker peptide, hG9NC(null), prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells. The suppression of cell growth was inhibited by lactose, but not by sucrose, indicating that b-galactoside binding is essential for hG9NC(null)-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of these genes are regulated by NF-jB, which plays a critical role in oncogenesis by HTLV-I. hG9NC(null) suppressed IjBa phosphorylation, resulting in suppression of NF-jB. Most importantly, treatment with hG9NC(null) (6.7 mg/kg injected intraperitoneally every day) reduced tumor formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into SCID mice. Our results suggest that hG9NC(null) could be a suitable agent for the management of ATL. ' 2007 Wiley-Liss, Inc.Key words: galectin-9; HTLV-I; ATL; NF-kB; apoptosis ATL is a unique malignancy of mature CD4-positive T cells caused by HTLV-I. 1-3 ATL is subclassified into 4 subtypes: acute, lymphoma, chronic and smoldering. In the relatively indolent smoldering and chronic types, the median survival time is more than 2 years. However, at present, there is no accepted curative therapy for ATL and the condition often progresses to death with a median survival time of 13 months in aggressive ATL. 4 Chemotherapies that are specifically known to be active against other lymphoid malignancies are ineffective for treating aggressive forms of ATL. Death is usually due to severe infection or hypercalcemia. Therefore, the establishment of new therapeutic strategies for ATL is very important.Galectins are a family of soluble b-galactoside binding animal lectins. To date, 14 members of the galectin family have been identified. Each member exhibits diverse biological functions and many of them appear to function in cellular homeostasis through regulation of cell adhesion, cell proliferation, cell death and chemoattraction. [5][6][7][8][9] The members can be classified into 3 subtypes according to their structures. The prototype (galectin-1, -2, -7, -10 and -13) and chimera type (galectin-3) galectins have a single CRD and they usually form a noncovalent homodimer resulting in homobifunctional sugar binding activity. Tandem-repeat type galectins (galectin-4, -8, -9 and -12) have two CRDs, which generally show different sugar binding specificities, joined by a linker peptide. This heterobifunctional property makes them capable of cros...

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

“…Among 14 mammalian galectins, galectin-9 (Gal9) has been shown to possess the anticancer properties by regulating various cellular functions, such as cell adhesion, cell proliferation, or apoptosis (8)(9)(10)(11)(12). These prompted us to investigate whether Gal9 can have an anti-CML effect through signaling cascades distinct from the pathway used by Bcr-Abl TKIs or by other commonly used anticancer agents.…”

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

“…[30][31][32][33] These findings lead us to suggest that both JNK and p38 pathways activation are the logical molecular targets for the development of new therapeutic strategies for MM. On the other hand, although earlier studies suggest that Anti-myeloma effect of galectin-9 T Kobayashi et al NF-kB signaling inactivation or the activation of Ca 2 þ -calpaincaspase-1 pathway are involved in the anti-proliferative effect of hGal9 in other cancers, 13,14,34 those were not the case in the myelomas (data not shown). These indicate that, as hGal9 recognizes various b-galactosides-containing surface molecules that may differ among cell types, its primary molecular targets may also differ according to cancer type.…”

“…[4][5][6][7][8][9][10] Moreover, recent studies have indentified anti-cancer properties of galectin-9 against several cancers. [11][12][13][14][15] In this study, we show the anti-multiple myeloma (MM) activity of a recombinant mutant form of human galectin-9 (hGal9) through the activation of c-Jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, those share crucial roles in the survival and death of myeloma cells. 16 …”

Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways

“…6B), indicating that the increased spacing and rotational flexibility of the CRDs were not the only features determining potency and target cell killing of the two galectins. In addition, a galectin-9 construct with most of the linker peptide removed was shown to retain potency in T cell death assays (55). The higher potency of galectin-9 could be due to the higher valency of multimeric galectin-9 compared with dimeric galectin-1, if galectin-9 oligomerizes via the N-terminal CRDs (54,56).…”