DPP8 is a novel therapeutic target for multiple myeloma
SCIENTIFIC REPORTS
Authors: Sato, Tsutomu; Tatekoshi, Ayumi; Takada, Kohichi; Iyama, Satoshi; Kamihara, Yusuke; Jawaid, Paras; Rehman, Mati Ur; Noguchi, Kyo; Kondo, Takashi; Kajikawa, Sayaka; Arita, Kotaro; Wada, Akinori; Murakami, Jun; Arai, Miho; Yasuda, Ichiro; Dang, Nam H.; Hatano, Ryo; Iwao, Noriaki; Ohnuma, Kei; Morimoto, Chikao
Abstract
Dipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment.
DPP9 enzymatic activity in hematopoietic cells is dispensable for mouse hematopoiesis
IMMUNOLOGY LETTERS
Authors: Kim, Munkyung; von Muenchow, Lilly; Le Meur, Thomas; Kueng, Benjamin; Gapp, Berangere; Weber, Delphine; Dietrich, William; Kovarik, Jiri; Rolink, Antonius G.; Ksiazek, Iwona
Abstract
Dipeptidyl peptidase 9 (DPP9) is a ubiquitously expressed intracellular prolyl peptidase implicated in immunoregulation. However, its physiological relevance in the immune system remains largely unknown. We investigated the role of DPP9 enzyme in immune system by characterizing DPP9 knock-in mice expressing a catalytically inactive S729A mutant of DPP9 enzyme (DPP9(ki/ki) mice). DPP9(ki/ki) mice show reduced number of lymphoid and myeloid cells in fetal liver and postnatal blood but their hematopoietic cells are fully functional and able to reconstitute lymphoid and myeloid lineages even in competitive mixed chimeras. These studies demonstrate that inactivation of DPP9 enzymatic activity does not lead to any perturbations in mouse hematopoiesis.
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