Cell death induced by dorsomorphin in adult T‐cell leukemia/lymphoma is AMPK‐independent
2020
Aikawa, Akiyoshi | Kozako, Tomohiro | Uchida, Yuichiro | Yoshimitsu, Makoto | Ishitsuka, Kenji | Ohsugi, Takeo | Honda, Shin‐ichiro
Adult T‐cell leukemia/lymphoma (ATL) is an aggressive T‐cell neoplasm with poor prognosis that develops after chronic infection with human T‐cell leukemia virus type 1 (HTLV‐1). Although AMP‐activated protein kinase (AMPK) is a critical cellular energy sensor, it has recently become clear that AMPK can act as a tumor regulator. Here, we assessed the expression of AMPK in primary ATL cells and the effects of dorsomorphin, an AMPK inhibitor, on primary ATL cells and HTLV‐1‐infected T‐cell lines. AMPK expression in acute and chronic ATL patients was significantly higher than in asymptomatic HTLV‐1 carriers and healthy donors. Dorsomorphin induced apoptosis in peripheral blood mononuclear cells from ATL patients. Dorsomorphin also induced dose‐ and time‐dependent apoptosis in HTLV‐1‐infected T‐cell lines. Dorsomorphin increased the production of intracellular reactive oxygen species (ROS) and induced ataxia telangiectasia‐mutated Ser1981 phosphorylation and p53 accumulation. These results indicated that dorsomorphin induces apoptosis via ROS‐mediated DNA damage in HTLV‐1‐infected T‐cell lines. Furthermore, dorsomorphin suppressed the growth of human ATL tumor xenografts in NOD/SCID mice. Together, these data suggest that AMPK could be a candidate therapeutic target for ATL and that dorsomorphin could be a therapeutic agent for ATL.
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