Kim Hyun-Kyoung, Lee Hwa-Young, Riaz Thoufiqul Alam, Bhattarai Kashi Raj, Chaudhary Manoj, Ahn Jin Hee, Jeong Jieun, Kim Hyung-Ryung, Chae Han-Jung
School of Pharmacy, Jeonbuk National University, Jeonju, 54896, Republic of Korea.
Non-Clinical Evaluation Center Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju, 54907, Republic of Korea.
Redox Biol. 2021 Apr;40:101853. doi: 10.1016/j.redox.2021.101853. Epub 2021 Jan 6.
Chalcone is a polyphenolic compound found abundantly in natural plant components. They have been acclaimed as potential antitumor compounds in multiple tumor cells. However, not much attention has been paid to elucidate its antitumor mechanism of action. Here, chalcone was demonstrated to trigger endoplasmic reticulum (ER) stress-induced apoptosis through sulfonation of IRE1α by ER-localized NADPH oxidase 4 (NOX4). IRE1α-sulfonation at a cysteine residue was shown to induce "regulated IRE1α-dependent decay" (RIDD) of mRNA rather than specific splicing of XBP1. The IRE1α sulfonation-induced RIDD degraded miR-23b, enhancing the expression of NOX4. The expression of NOX4 was also upregulated in breast, and prostate cancer tissue. In chalcone-administered mice in vivo, tumor growth was regressed by the consistent mechanisms "NOX4-IRE1α sulfonation-RIDD". Similarly, NOX4 activation and IRE1α sulfonation were also highly increased under severe ER stress conditions. Together, these findings suggest chalcone as a lead anticancer compound where it acts through NOX4-IRE1α-RIDD-miR-23b axis providing a promising vision of chalcone derivatives' anticancer mechanism.
查尔酮是一种在天然植物成分中大量存在的多酚类化合物。它们在多种肿瘤细胞中被誉为潜在的抗肿瘤化合物。然而，对于阐明其抗肿瘤作用机制的关注并不多。在此，研究表明查尔酮通过内质网定位的NADPH氧化酶4（NOX4）对IRE1α进行磺化，从而触发内质网（ER）应激诱导的细胞凋亡。在一个半胱氨酸残基处的IRE1α磺化被证明会诱导mRNA的“受调控的IRE1α依赖性降解”（RIDD），而非XBP1的特异性剪接。IRE1α磺化诱导的RIDD会降解miR-23b，从而增强NOX4的表达。在乳腺癌和前列腺癌组织中，NOX4的表达也会上调。在体内给予查尔酮的小鼠中，肿瘤生长通过“NOX4-IRE1α磺化-RIDD”这一一致机制而消退。同样，在严重内质网应激条件下，NOX4的激活和IRE1α的磺化也会显著增加。总之，这些发现表明查尔酮作为一种先导抗癌化合物，通过NOX4-IRE1α-RIDD-miR-23b轴发挥作用，为查尔酮衍生物的抗癌机制提供了一个有前景的设想。
