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Lupenone attenuates thapsigargin-induced endoplasmic reticulum stress and apoptosis in pancreatic beta cells possibly through inhibition of protein tyrosine kinase 2 activity

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Author(s)
Seung-Eun SongSu-Kyung ShinYong-Woon KimYoung Rok DoAe Kyoung LimJae-Hoon BaeGil-Saeng JeongSeung-Soon ImDae-Kyu Song
Keimyung Author(s)
Do, Young RokBae, Jae HoonIm, Seung SoonSong, Dae Kyu
Department
Dept. of Internal Medicine (내과학)
Dept. of Physiology (생리학)
Journal Title
Life Sci
Issued Date
2023
Volume
332
Keyword
2-Aminoethoxydiphenyl borate (PubChem CID: 1598)4-Phenylbutyric acid (PubChem CID: 4775)ApoptosisBeta-cellCyclopiazonic acid (PubChem CID: 54695722)ER stressKN-93 (PubChem CID: 5312122)LupenoneLupenone (PubChem CID: 92158)Protein tyrosine kinase 2SP600125 (PubChem CID: 8515)Sodium orthovanadate (PubChem CID: 61671)Store-operated calcium entryStreptozotocin (PubChem CID: 29327)Thapsigargin (PubChem CID: 446378)W-7 (PubChem CID: 124887)
Abstract
Aims:
Prolonged high levels of cytokines, glucose, or free fatty acids are associated with diabetes, elevation of cytosolic Ca2+ concentration ([Ca2+]C), and depletion of Ca2+ concentration in the endoplasmic reticulum (ER) of pancreatic beta cells. This Ca2+ imbalance induces ER stress and apoptosis. Lupenone, a lupan-type triterpenoid, is beneficial in diabetes; however, its mechanism of action is yet to be clarified. This study evaluated the protective mechanism of lupenone against thapsigargin-induced ER stress and apoptosis in pancreatic beta cells.

Materials and methods:
MIN6, INS-1, and native mouse islet cells were used. Western blot for protein expressions, measurement of [Ca2+]C, and in vivo glucose tolerance test were mainly performed.

Key findings:
Thapsigargin increased the protein levels of cleaved caspase 3, cleaved PARP, and the phosphorylated form of JNK, ATF4, and CHOP. Thapsigargin increased the interaction between stromal interaction molecule1 (Stim1) and Orai1, enhancing store-operated calcium entry (SOCE). SOCE is further activated by protein tyrosine kinase 2 (Pyk2), which is Ca2+-dependent and phosphorylates the tyrosine residue at Y361 in Stim1. Lupenone inhibited thapsigargin-mediated Pyk2 activation, suppressed [Ca2+]C, ER stress, and apoptosis. Lupenone restored impaired glucose-stimulated insulin secretion effectuated by thapsigargin and glucose intolerance in a low-dose streptozotocin-induced diabetic mouse model.

Significance:
These results suggested that lupenone attenuated thapsigargin-induced ER stress and apoptosis by inhibiting SOCE; this may be due to the hindrance of Pyk2-mediated Stim1 tyrosine phosphorylation. In beta cells that are inevitably exposed to frequent [Ca2+]C elevation, the attenuation of abnormally high SOCE would be beneficial for their survival.
Keimyung Author(s)(Kor)
도영록
배재훈
임승순
송대규
Publisher
School of Medicine (의과대학)
Type
Article
ISSN
1879-0631
Source
https://www.sciencedirect.com/science/article/pii/S0024320523007427
DOI
10.1016/j.lfs.2023.122107
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/45276
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
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