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Rosmarinic Acid Decreases the Malignancy of Pancreatic Cancer Through Inhibiting Gli1 Signaling
Xiang Zhou1, Weiming Wang2, Zhaofeng Li3
1Department of Breast Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Background:
Rosmarinic acid (RA) has been shown to exert anti-tumor effects on various types of cancer. However, its roles in the treatment of pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanisms remain elusive.
Purpose:
The present study aimed to investigate the therapeutic effects of RA on PDAC as well as the underlying mechanisms.
Study Design:
Evaluation of the effects of RA on PDAC malignancy both in vitro and in vivo.
Methods:
Cell counting kit 8 (CCK8) assay, colony formation assay, 5-Ethynyl-2'-deoxyuridine (EDU) incorporation assay, cell cycle analysis, and apoptosis assay were conducted to assess the inhibitory effect of RA on PDAC cell proliferation. Meanwhile, western blotting and RT-qPCR assay were performed to detect the target gene expression at protein and mRNA levels, respectively. Moreover, the in vivo anti-tumor activities of RA were assayed in an xenograft mouse model of PDAC.
Results:
RA dramatically down-regulated Gli1 and its downstream targets. Further studies showed that RA prevents the nuclear translocation of Gli1, while promoting the degradation of cytosolic Gli1 via the proteasome pathway. Moreover, we observed that RA induced G1/S cell cycle arrest and apoptosis in the PDAC cells through regulating the expression of P21, P27, CDK2, Cyclin E, Bax, and Bcl-2, it inhibited the PDAC cell migration and invasion via E-cadherin and MMP-9. Notably, Gli1 overexpression markedly reversed the above RA-induced effects on PDAC cells, whereas Gli1 knockdown enhanced the effects. Additionally, the in vivo assays demonstrated that RA suppresses the tumor growth of PDAC presumably by inhibiting Gli1.
Conclusion:
We provided evidence that RA restrained the nuclear translocation of Gli1 and facilitates Gli1 degradation via proteasome pathway, reducing the malignancy of PDAC cells. These findings implicated RA as a therapeutic agent for PDAC.
Insights
Rosmarinic acid (RA) effectively combats pancreatic ductal adenocarcinoma (PDAC) by inhibiting Gli1, a key cancer-promoting protein. This study reveals RA
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) remains a challenging cancer with limited therapeutic options.
- Rosmarinic acid (RA) exhibits known anti-tumor properties, but its specific role and mechanisms in PDAC are not well understood.
Purpose of the Study:
- To investigate the therapeutic potential of Rosmarinic acid (RA) against pancreatic ductal adenocarcinoma (PDAC).
- To elucidate the underlying molecular mechanisms by which RA exerts its anti-PDAC effects.
Main Methods:
- In vitro assays (CCK8, colony formation, EDU, cell cycle, apoptosis) assessed RA's impact on PDAC cell proliferation, cell cycle, and apoptosis.
- Western blotting and RT-qPCR analyzed target gene expression.
- In vivo studies utilized a PDAC xenograft mouse model to evaluate anti-tumor activity.
Main Results:
- RA significantly down-regulated Gli1 expression and its downstream targets in PDAC cells.
- RA inhibited PDAC cell proliferation, migration, and invasion by inducing G1/S cell cycle arrest and apoptosis.
- RA treatment prevented Gli1 nuclear translocation and promoted its proteasomal degradation, suppressing tumor growth in vivo.
Conclusions:
- Rosmarinic acid (RA) demonstrates significant therapeutic potential against pancreatic ductal adenocarcinoma (PDAC).
- RA functions by inhibiting Gli1 nuclear translocation and promoting its degradation, thereby reducing PDAC malignancy.
- These findings position RA as a promising candidate for PDAC treatment.
