Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
FASEB J. 2023 Oct;37(10):e23143. doi: 10.1096/fj.202300474R.
Cuproptosis, a new type of copper-induced cell death, is involved in the antitumor activity and resistance of multiple chemotherapeutic drugs. Our previous study revealed that adrenomedullin (ADM) was engaged in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). However, it has yet to be investigated whether and how ADM regulates sunitinib resistance by cuproptosis. This study found that the ADM expression was elevated in sunitinib-resistant ccRCC tissues and cells. Furthermore, the upregulation of ADM significantly enhanced the chemoresistance of sunitinib compared with their respective control. Moreover, cuproptosis was involved in ADM-regulated sunitinib resistance by inhibiting mammalian ferredoxin 1 (FDX1) expression. Mechanically, the upregulated ADM activates the p38/MAPK signaling pathway to promote Forkhead box O3 (FOXO3) phosphorylation and its entry into the nucleus. Consequently, the increased FOXO3 in the nucleus inhibited FDX1 transcription and cell cuproptosis, promoting chemoresistance. Collectively, cuproptosis has a critical effector role in ccRCC progress and chemoresistance and thus is a relevant target to eradicate the cell population of sunitinib resistance.
铜死亡是一种新型的铜诱导细胞死亡方式，参与多种化疗药物的抗肿瘤活性和耐药性。我们之前的研究表明，肾上腺髓质素（ADM）参与了肾透明细胞癌（ccRCC）中舒尼替尼的耐药性。然而，ADM 是否以及如何通过铜死亡调节舒尼替尼耐药性仍有待研究。本研究发现 ADM 在舒尼替尼耐药性 ccRCC 组织和细胞中表达上调。此外，与各自对照相比，ADM 的上调显著增强了舒尼替尼的化学耐药性。此外，铜死亡通过抑制哺乳动物铁氧还蛋白 1（FDX1）表达参与 ADM 调节的舒尼替尼耐药性。机制上，上调的 ADM 激活 p38/MAPK 信号通路，促进叉头框 O3（FOXO3）磷酸化及其进入细胞核。因此，核内增加的 FOXO3 抑制了 FDX1 转录和细胞铜死亡，促进了化学耐药性。总之，铜死亡在 ccRCC 的进展和化学耐药性中起着关键的效应子作用，因此是消除舒尼替尼耐药细胞群的相关靶点。
