Mitochondrial ALDH2 improves ß‐cell survival and function against doxorubicin‐induced apoptosis by targeting CK2 signaling

Autor: Udayakumar Karunakaran, Eun Yeong Ha, Suma Elumalai, Kyu Chang Won, Jun Sung Moon
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Journal of Diabetes Investigation, Vol 15, Iss 6, Pp 684-692 (2024)
Druh dokumentu: article
ISSN: 2040-1124
2040-1116
15743098
DOI: 10.1111/jdi.14230
Popis: ABSTRACT Aims The aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of β‐cell dysfunction and to explore its relationship with mitochondrial aldehyde dehydrogenase‐2 (ALDH2). Materials and Methods In order to investigate this hypothesis, doxorubicin was administered to INS‐1 cells, a rat insulinoma cell line, either with or without several target protein activators and inhibitors. ALDH2 activity was detected with a commercial kit and protein levels were determined with western blot. Mitochondrial ROS, membrane potential, and lipid ROS were determined by commercial fluorescent probes. The cell viability was measured by CCK‐assay. Results Exposure of INS‐1 cells to doxorubicin decreased active insulin signaling resulting in elevated ALDH2 degradation, compared with control cells by the induction of acid sphingomyelinase mediated ceramide induction. Further, ceramide induction potentiated doxorubicin induced mitochondrial dysfunction. Treatment with the ALDH2 agonist, ALDA1, blocked doxorubicin‐induced acid sphingomyelinase activation which significantly blocked ceramide induction and mitochondrial dysfunction mediated cell death. Treatment with the ALDH2 agonist, ALDA1, stimulated casein kinase‐2 (CK2) mediated insulin signaling activation. CK2 silencing neutralized the function of ALDH2 in the doxorubicin treated INS‐1 cells. Conclusions Mitochondrial ALDH2 activation could inhibit the progression of doxorubicin induced pancreatic β‐cell dysfunction by inhibiting the acid sphingomyelinase induction of ceramide, by regulating the activation of CK2 signaling. Our research lays the foundation of ALDH2 activation as a therapeutic target for the precise treatment of chemotherapy drug induced β‐cell dysfunction.
Databáze: Directory of Open Access Journals
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