Targeting p53 Improves Drug Resistance in Mantle Cell Lymphoma By Regulating Mitophagy-Dependent Ferroptosis

Background:Drug resistance in mantle cell lymphoma (MCL) represents a critical challenge in clinical practice. Our preliminary findings indicated a high p53 mutation rate in drug-resistant MCL patients, accompanied by diminished expression of mitophagy-related markers PINK1 and Parkin, and elevated level of the ferroptosis-related marker GPX4 in these resistant cases. This study aimed to explore the regulatory relationship between p53, mitophagy, and ferroptosis in MCL.

Methods:The expression ofPINK1, Parkin and GPX4 was detected in MCL patients and MCL cell lines (Jeko, Mino, Rec1, Z138 and JVM2 cells).The correlation between p53 expression and the expression of PINK1, Parkin, and GPX4 in MCL patients was analyzed via GEO database. MCL cell lines were treated with APR-246, an agent targeting mutant p53, and then cell proliferation, gene expression and ROS level were determined by CCK-8, qPCR and flow cytometry. The regulatory mechanism between p53 and PINK1 was revealed by CUT&Tag technology.

Results: Compared with chemotherapy sensitive MCL patients, chemotherapy resistant MCL patients have lower expression of mitophagy-related genes PINK1 and Parkin, and higher expression of ferroptosis-related gene GPX4. Low expression of Parkin and high expression of GPX4 were associated with poor prognosis in MCL patients. Besides, p53 expression was positively correlated with PINK1 expression and negatively correlated with GPX4 expression in GSE93291 database. In p53-mutant MCL cells (Mino and Rec1), the expression of PINK1 and Parkin was lower than that of p53-deficient MCL cells (Jeko) and p53-wild type MCL cells (Z138 and JVM2), while the expression of GPX4 and SLC7A11 was higher than that of p53-deficient and p53-wild type MCL cells. APR-246 showed significant inhibitory effect on cell proliferation of p53-mutant MCL cells, while its inhibitory effect was not strong on p53-deficient and p53-wild type cells. After APR-246 intervention, the expression of PINK1 and Parkin was significantly increased, the expression of GPX4 and SLC7A11 was significantly decreased, and ROS accumulation was observed in p53-mutant cells. However, these phenomena were not occurred in p53-deficient and p53-wild type cells. CUT&Tag assay revealed mechanistically that PINK1 was transcriptionally activated by p53.

Conclusions:Our study elucidates the specific mechanism by which targeting mutant p53 could improve drug resistance in MCL by regulating mitophagy-dependent ferroptosis, and provides a new therapeutic strategy for chemotherapy resistant MCL patients.

No relevant conflicts of interest to declare.