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Published on: March 30, 2019
MiR-29 and MiR-140 regulate TRAIL-induced drug tolerance in lung cancer
Suyeon Kim1, Ki Wook Lee1, Yongjin Yoo2
1Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in lung cancer is linked to miR-29 and miR-140 epigenetic changes. Restoring these microRNAs may re-sensitize tumors to TRAIL therapy.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits anti-cancer potential but faces limitations due to drug resistance.
- Acquired resistance to TRAIL is a significant obstacle, potentially mediated by intermediate drug tolerance.
- MicroRNA (miRNA)-dependent epigenetic modifications are implicated in TRAIL-induced drug tolerance (TDT).
Purpose of the Study:
- To investigate the role of miRNA-dependent epigenetic modifications in TRAIL resistance.
- To identify specific miRNAs and their targets involved in TRAIL-tolerant states in lung cancer.
- To explore therapeutic strategies for overcoming TRAIL resistance in lung cancer.
Main Methods:
- Transcriptomic analysis of TRAIL-tolerant cells to identify differentially expressed miRNAs and their targets.
- Validation of miRNA-target interactions and their association with TRAIL sensitivity in lung cancer cell lines and patient samples.
- Correlation analysis between TRAIL sensitivity, RSK2 mRNA expression, and NF-κB activation.
Main Results:
- Activation of miR-29 target genes was observed in TDT cells, indicating an oncogenic signature in lung cancer.
- Restored TRAIL sensitivity correlated with miR-29ac and miR-140-5p expression, which suppress oncogenic RSK2 (p90 ribosomal S6 kinase).
- Increased RSK2 mRNA expression was linked to NF-κB activation, a known factor in TRAIL resistance.
Conclusions:
- MiRNA-dependent epigenetic modification drives drug tolerance in TRAIL-treated lung cancer.
- miR-29ac and miR-140-5p play a tumor-suppressive role by inhibiting RSK2 and maintaining TRAIL sensitivity.
- Inhibiting miR-29ac and miR-140-5p could be a strategy to enhance TRAIL efficacy and durability in lung cancer treatment.
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