Lysosome Fe release is responsible for etoposide- and cisplatin-induced stemness of small cell lung cancer cells.

Iron metabolism has been shown to hand over cancer stem cell, which is regarded as the root of tumor progression, recurrence and chemoresistance. This study aims to explore whether iron metabolism is involved in etoposide- and cisplatin-induced stemness in small cell lung cancer (SCLC) cells. Here, analysis on tumor-sphere formation and stemness marker expression is performed to determine whether etoposide and cisplatin can induce SCLC cell stemness. Online dataset analysis is constructed to determine the correlation between iron transportation and the survival of lung cancer patients. Chromatin immunoprecipitation combined with rescuing experiments are carried out to reveal the underlying mechanisms. Additionally, the non-lethal doses of etoposide and cisplatin can induce SCLC cell stemness in a concentration-dependent manner and reduce the lysosome iron concentration dependent on Ferritin expression, which is positively regulated by HIF-1α/β. Moreover, HIF-1α/β can directly bind to Ferritin promoter region. This HIF/Ferritin axis is responsible for etoposide- and cisplatin-induced iron reduction in lysosomes and stemness of SCLC cells. This work demonstrates that iron in lysosomes is essential for etoposide and cisplatin-induced stemness of SCLC cells, which is regulated by the HIF/Ferritin axis.