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PinX1 inhibits migrasomes-mediated mitochondrial transfer to confer cisplatin sensitivity in nasopharyngeal carcinoma
Juan Zhang1, Junqi Wang2, Tingfeng Liang1
1Department of Otorhinolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Abstract:
Chemotherapy resistance is a major factor contributing to the failure of nasopharyngeal carcinoma (NPC) treatment. Migrasomes can export damaged mitochondria out of the cell, and the timely removal of damaged mitochondria is key to cancer cell resistance. However, whether migrasomes regulate tumor resistance remains unknown. Here, we elucidated the role and mechanism of migrasomes in chemoresistance of NPC. We found that the formation of migrasomes was increased in cisplatin-resistant NPC cells, and inhibiting migrasome formation reduced cisplatin resistance. PinX1 was lowly expressed in tumor tissues of patients with high migrasome scores. Upstream mechanism analyses showed that TP53 was effectively bound to the promoter of PinX1, thereby enhancing its transcriptional activity. Knockdown of PinX1 facilitated migrasome formation via its telomerase inhibitory domain 252-328aa region binding to Rab11a, which relied on serine residues at the N-terminal 25aa site for promoting migrasome formation. Mechanistically, PinX1 recruited RanBP2 to induce the SUMOylation of Rab11a, leading to the degradation of Rab11a at the K207 site. Furthermore, PinX1 reduced cancer cell energy metabolism by inhibiting the export of damaged mitochondria via migrasomes. Collectively, TP53-activated PinX1 recruits RanBP2 to Rab11a, triggering Rab11a K207 SUMOylation and degradation, leading to impaired migrasome formation and mitochondrial transfer, and ultimately suppresses cisplatin resistance in NPC. Our study provides a new target for clinical reversal of chemotherapy resistance in patients with NPC.
Insights
Chemotherapy resistance in nasopharyngeal carcinoma (NPC) is linked to migrasomes. Targeting the TP53-PinX1-Rab11a pathway can reduce migrasome formation, overcoming cisplatin resistance in NPC.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Chemotherapy resistance significantly hinders nasopharyngeal carcinoma (NPC) treatment outcomes.
- Migrasomes, involved in removing damaged mitochondria, are implicated in cancer cell resistance, but their role in NPC chemoresistance is unclear.
Purpose of the Study:
- To investigate the role and underlying mechanisms of migrasomes in cisplatin resistance in NPC.
- To identify potential therapeutic targets for reversing chemotherapy resistance in NPC.
Main Methods:
- Comparative analysis of migrasome formation in cisplatin-sensitive and resistant NPC cells.
- Investigation of the regulatory roles of PinX1 and TP53 in migrasome formation and chemoresistance.
- Molecular analyses including gene expression, protein binding, SUMOylation, and degradation assays.
- Assessment of mitochondrial export and cellular energy metabolism.
Main Results:
- Migrasome formation increased in cisplatin-resistant NPC cells; inhibition reduced resistance.
- TP53 enhances PinX1 transcription; low PinX1 expression correlates with high migrasome scores in patients.
- PinX1 knockdown promotes migrasome formation by interacting with Rab11a, leading to Rab11a SUMOylation and degradation.
- PinX1 suppresses cisplatin resistance by inhibiting migrasome-mediated damaged mitochondria export, reducing cancer cell energy metabolism.
Conclusions:
- The TP53-PinX1 pathway regulates migrasome formation and mitochondrial export, impacting NPC chemoresistance.
- PinX1 activation by TP53 leads to Rab11a degradation, impairing migrasome function and suppressing cisplatin resistance.
- This pathway represents a novel therapeutic target for overcoming chemotherapy resistance in NPC.
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