Astragaloside IV Overcomes Anlotinib Resistance in Non-small Cell Lung Cancer through miR-181a-3p/UPR-ERAD Axis
Lihuai Wang1, Tonglin Sun1, Xiao Yang1
1Department of Oncology, the First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha 410000, Hunan Province, China.
Background:
Astragaloside IV (AS-IV) has been shown to have a curative effect on non-small cell lung cancer (NSCLC). This study aimed to elucidate the role of AS-IV in NSCLC cell anlotinib resistance (AR).
Methods:
The NSCLC/AR cells, resistant to anlotinib, have been produced. The role of AS-IV in the AR of NSCLC cells about the miR-181a-3p/unfolded protein response (UPR)- endoplasmic reticulum associated degradation (ERAD) pathway was then discussed by treating the cells with anlotinib or AS-IV, or by manipulating them with inhibitors or mimics of miR- 181a-3p, HRD1 or Derlin-1 overexpression plasmids.
Results:
We found that AS-IV could suppress the AR of NSCLC cells. In addition, miR-181a- 3p was elevated in NSCLC/AR cells. Functionally, AS-IV limited the AR of NSCLC cells by reducing miR-181a-3p. Further, activation of the UPR-ERAD pathway was correlated with AR in NSCLC cells. Increased sensitivity of NSCLC cells to anlotinib caused by miR-181a-3p inhibitor could be reversed by overexpression of HRD1 or Derlin-1.
Conclusion:
This research revealed a promising NSCLC/AR treatment approach by showing that AS-IV exposed NSCLC cells to anlotinib by inhibiting the miR-181a-3p/UPR-ERAD axis.
Insights
Astragaloside IV (AS-IV) suppresses anlotinib resistance in non-small cell lung cancer (NSCLC) by inhibiting the miR-181a-3p/unfolded protein response-endoplasmic reticulum associated degradation (UPR-ERAD) pathway, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Astragaloside IV (AS-IV) demonstrates therapeutic potential for non-small cell lung cancer (NSCLC).
- Anlotinib resistance (AR) is a significant challenge in NSCLC treatment.
- The role of AS-IV in overcoming AR in NSCLC requires further investigation.
Purpose of the Study:
- To investigate the role of AS-IV in non-small cell lung cancer anlotinib resistance (NSCLC/AR).
- To elucidate the underlying molecular mechanisms involving the miR-181a-3p/unfolded protein response (UPR)-endoplasmic reticulum associated degradation (ERAD) pathway.
Main Methods:
- Generated NSCLC cells with acquired anlotinib resistance (NSCLC/AR).
- Treated cells with anlotinib, AS-IV, or manipulated miR-181a-3p, HRD1, and Derlin-1 expression using inhibitors and overexpression plasmids.
- Assessed the impact of AS-IV and pathway modulation on NSCLC/AR.
Main Results:
- AS-IV significantly suppressed anlotinib resistance in NSCLC cells.
- miR-181a-3p levels were elevated in NSCLC/AR cells, and AS-IV reduced these levels.
- Activation of the UPR-ERAD pathway correlated with AR; inhibiting miR-181a-3p increased sensitivity to anlotinib, which was reversed by HRD1 or Derlin-1 overexpression.
Conclusions:
- AS-IV effectively overcomes anlotinib resistance in NSCLC.
- The mechanism involves the inhibition of the miR-181a-3p/UPR-ERAD axis.
- This study presents AS-IV as a promising therapeutic agent for NSCLC with anlotinib resistance.
