Alpinumisoflavone Activates Disruption of Calcium Homeostasis, Mitochondria and Autophagosome to Suppress Development of Endometriosis

Abstract

Alpinumisoflavone is an isoflavonoid extracted from the Cudrania tricuspidate fruit and Genista pichisermolliana. It has various physiological functions, such as anti-inflammation, anti-proliferation, and apoptosis, in malignant tumors. However, the effect of alpinumisoflavone is still not known in chronic diseases and other benign reproductive diseases, such as endometriosis. In this study, we examined the cell death effects of alpinumisoflavone on the endometriosis cell lines, End1/E6E7 and VK2/E6E7. Results indicated that alpinumisoflavone inhibited cell migration and proliferation and led to cell cycle arrest, depolarization of mitochondria membrane potential, apoptosis, and disruption of calcium homeostasis in the endometriosis cell lines. However, the cellular proliferation of normal uterine epithelial cells was not changed by alpinumisoflavone. The alteration in Ca2+ levels was estimated in fluo-4 AM-stained End1/E6E7 and VK2/E6E7 cells after alpinumisoflavone treatment with or without calcium inhibitor, 2-aminoethoxydiphenyl borate (2-APB). The results indicated that a combination of alpinumisoflavone and a calcium inhibitor reduced the calcium accumulation in the cytosol of endometriosis cells. Additionally, alpinumisoflavone decreased oxidative phosphorylation (OXPHOS) in the endometriotic cells. Moreover, protein expression analysis revealed that alpinumisoflavone inactivated AKT signaling pathways, whereas it increased MAPK, ER stress, and autophagy regulatory proteins in End1/E6E7 and VK2/E6E7 cell lines. In summary, our results suggested that alpinumisoflavone could be a promising effective management agent or an adjuvant therapy for benign disease endometriosis.

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“…The ER is a large and dynamic organelle that plays a role in protein synthesis, transport, carbohydrate metabolism, and calcium storage. Moreover, the ER covers approximately 20% of the mitochondrial surface so that both organelles conduct key intracellular functions together, such as regulating cell survival, energy metabolism, and calcium homeostasis [ 27 , 28 , 29 ]. First, in the aspect of calcium homeostasis, there are ryanodine receptors (RyR), IP 3 R, and sarcoendoplasmic reticulum calcium ATPase in the ER membrane.…”

SLC8A1, a novel prognostic biomarker and immunotherapy target in RSA and UCEC based on scRNA-seq and pan-cancer analysis

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Regulated Cell Death in Endometriosis

“…Açai Berry administration was able to modulate autophagy, oxidative stress, and apoptosis in mouse endometriosis models [114]. Alpinumisoflavone is an isoflavonoid extracted from fruit that inhibits cell migration and proliferation and leads to cell apoptosis in endometriosis cell lines [115].…”