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PRMT5 promotes chemotherapy-induced neuroendocrine differentiation in NSCLC
Qi Shen1,2, Yi Liu1,3, Xuehong Deng1
1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, West Lafayette, Indiana, USA.
Background:
In response to therapeutic treatments, cancer cells can exhibit a variety of resistance phenotypes including neuroendocrine differentiation (NED). NED is a process by which cancer cells can transdifferentiate into neuroendocrine-like cells in response to treatments, and is now widely accepted as a key mechanism of acquired therapy resistance. Recent clinical evidence has suggested that non-small cell lung cancer (NSCLC) can also transform into small cell lung cancer (SCLC) in patients treated with EGFR inhibitors. However, whether chemotherapy induces NED to confer therapy resistance in NSCLC remains unknown.
Methods:
We evaluated whether NSCLC cells can undergo NED in response to chemotherapeutic agents etoposide and cisplatin. By Knock-down of PRMT5 or pharmacological inhibition of PRMT5 to identify its role in the NED process.
Results:
We observed that both etoposide and cisplatin can induce NED in multiple NSCLC cell lines. Mechanistically, we identified protein arginine methyltransferase 5 (PRMT5) as a critical mediator of chemotherapy-induced NED. Significantly, the knock-down of PRMT5 or pharmacological inhibition of PRMT5 suppressed the induction of NED and increased the sensitivity to chemotherapy.
Conclusion:
Taken together, our results suggest that targeting PRMT5 may be explored as a chemosensitization approach by inhibiting chemotherapy-induced NED.
Insights
Chemotherapy can induce neuroendocrine differentiation (NED) in non-small cell lung cancer (NSCLC) cells, a process mediated by PRMT5. Targeting PRMT5 may enhance chemotherapy effectiveness by blocking this resistance mechanism.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Cancer cells can develop resistance to therapy through various mechanisms, including neuroendocrine differentiation (NED).
- Non-small cell lung cancer (NSCLC) has been observed to transform into small cell lung cancer (SCLC) following EGFR inhibitor treatment.
- The role of chemotherapy in inducing NED and therapy resistance in NSCLC is not well understood.
Purpose of the Study:
- To investigate if NSCLC cells undergo NED when exposed to chemotherapy agents.
- To identify the role of protein arginine methyltransferase 5 (PRMT5) in chemotherapy-induced NED.
Main Methods:
- NSCLC cell lines were treated with etoposide and cisplatin.
- PRMT5 was inhibited through gene knockdown or pharmacological agents.
Main Results:
- Etoposide and cisplatin were found to induce NED in multiple NSCLC cell lines.
- PRMT5 was identified as a key mediator in this chemotherapy-induced NED process.
- Inhibiting PRMT5 reduced NED induction and improved NSCLC sensitivity to chemotherapy.
Conclusions:
- Chemotherapy can induce NED in NSCLC, contributing to treatment resistance.
- PRMT5 plays a critical role in mediating chemotherapy-induced NED.
- Targeting PRMT5 presents a potential strategy for chemosensitization by preventing NED.
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