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Inhibition of SMYD2 Sensitized Cisplatin to Resistant Cells in NSCLC Through Activating p53 Pathway
Lei Shang1,2, Minjie Wei1
1School of Pharmacy, China Medical University, Shenyang, China.
Abstract:
The protein lysine methyltransferase SMYD2 has recently emerged as a new enzyme modulate gene transcription or signaling pathways, and involved into tumor progression. However, the role of SMYD2 in drug resistant is still not known. Here, we found that inhibition of SMYD2 by specific inhibitor could enhance the cell sensitivity to cisplatin (CDDP), but not paclitaxel, NVB, and VCR in non-small cell lung cancer (NSCLC). Further study showed that SMYD2 and its substrates were overexpressed in NSCLC resistant cells, and the inhibition of SMYD2 or knockdown by specific siRNA could reverse the cell resistance to cisplatin treatment in NSCLC/CDDP cells. In addition, our data indicated that the inhibition or knockdown SMYD2 inhibit tumor sphere formation and reduce cell migration in NSCLC/CDDP cells, but not in NSCLC parental cells. Mechanistically, inhibition of SMYD2 could enhance p53 pathway activity and induce cell apoptosis through regulating its target genes, including p21, GADD45, and Bax. On the contrary, the sensitivity of cells to cisplatin was decreased after knockdown p53 or in p53 deletion NSCLC cells. The synergistically action was further confirmed by in vivo experiments. Taken together, our results demonstrate SMYD2 is involved into cisplatin resistance through regulating p53 pathway, and might become a promising therapeutic target for cisplatin resistance in NSCLC.
Insights
SMYD2 inhibition enhances cisplatin sensitivity in non-small cell lung cancer (NSCLC) by activating the p53 pathway. This finding suggests SMYD2 as a potential therapeutic target for overcoming cisplatin resistance in NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- SMYD2 (the 'another proline-rich domain protein' methyltransferase) is implicated in gene transcription, signaling, and tumor progression.
- The role of SMYD2 in acquired drug resistance, particularly in non-small cell lung cancer (NSCLC), remains largely unexplored.
Purpose of the Study:
- To investigate the role of SMYD2 in cisplatin resistance in non-small cell lung cancer (NSCLC).
- To explore the potential of targeting SMYD2 as a therapeutic strategy to overcome cisplatin resistance in NSCLC.
Main Methods:
- Utilized specific SMYD2 inhibitors and siRNA for knockdown experiments in NSCLC and cisplatin-resistant NSCLC cell lines (NSCLC/CDDP).
- Assessed cell sensitivity to various chemotherapeutic agents, including cisplatin (CDDP).
- Investigated effects on tumor sphere formation, cell migration, apoptosis, and the p53 signaling pathway.
Main Results:
- SMYD2 inhibition sensitized NSCLC cells to cisplatin but not other tested drugs.
- SMYD2 and its substrates were overexpressed in resistant NSCLC cells; inhibition/knockdown reversed resistance.
- SMYD2 targeting inhibited tumor sphere formation and migration in resistant cells, enhanced p53 pathway activity, and induced apoptosis.
- p53 pathway modulation directly impacted cisplatin sensitivity, confirmed by in vivo studies.
Conclusions:
- SMYD2 plays a critical role in conferring cisplatin resistance in NSCLC through regulation of the p53 pathway.
- Targeting SMYD2 presents a promising therapeutic avenue for overcoming cisplatin resistance in non-small cell lung cancer.
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