Methionine restriction inhibits pancreatic cancer proliferation while suppressing JAK2/STAT3 pathway
Manabu Maebashi1, Kentaro Miyake1, Jun Yamamoto1
1Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Background:
Methionine restriction (MR) has been demonstrated to exhibit anti-tumor effects in various types of cancer, including pancreatic cancer (PC). However, the detailed mechanism induced by MR remains still unclear. This study aims to reveal the underlying mechanism of MR on PC by proteomic analysis.
Material & Methods:
Human PC cell lines were cultured in both standard and MR media to evaluate the effect of MR. The differences in protein expression were evaluated through proteomic analysis. Ingenuity Pathway Analysis (IPA) was performed to identify proteins potentially associated with tumor growth in vitro. The proteins associated with the anti-tumor effect were validated using western blotting, real-time PCR, and ELISA. An experimental model involving subcutaneous PC mice was established for the assessment of the effectiveness of the MR diet and the expression of target proteins through immunohistochemical staining.
Results:
Cell proliferation was suppressed in the MR media compared to the standard media. IPA analysis showed that STAT3 was decreased in the Apoptotic Pathway of Pancreatic Cancer Cell lines in the MR group. Western blotting showed MR decreased STAT3 expression. Real-time PCR showed that MR decreased JAK2 and STAT3 mRNA expression in Panc-1 and Mia-PaCa 2, but not in Capan-1. ELISA revealed that NF-kB expression was decreased in the MR group. In the in vivo study, the final estimated tumor volume in the MR group was significantly lower than the control group (p < 0.01). Immunostaining of resected specimens showed that STAT3 expression was suppressed in the MR group.
Conclusion:
MR suppressed the JAK2/STAT3 pathway and decreased NF-kB in some PC cell lines.
Insights
Methionine restriction (MR) inhibits pancreatic cancer (PC) growth by suppressing the JAK2/STAT3 pathway and decreasing NF-kB. This study reveals MR’s anti-tumor mechanism in PC.
Area of Science:
- Oncology
- Molecular Biology
- Nutritional Science
Background:
- Methionine restriction (MR) shows anti-tumor effects in various cancers, including pancreatic cancer (PC).
- The precise molecular mechanisms underlying MR's anti-cancer activity in PC are not fully understood.
- Proteomic analysis is employed to elucidate MR's impact on PC.
Purpose of the Study:
- To investigate the underlying molecular mechanisms of methionine restriction (MR) in pancreatic cancer (PC).
- To identify key proteins and pathways affected by MR in PC cell lines and in vivo models.
Main Methods:
- Human PC cell lines were cultured under standard and MR conditions.
- Proteomic analysis and Ingenuity Pathway Analysis (IPA) were used to identify differentially expressed proteins.
- Validation was performed using western blotting, real-time PCR, ELISA, and immunohistochemistry in an in vivo mouse model.
Main Results:
- MR significantly suppressed pancreatic cancer cell proliferation in vitro.
- Proteomic and validation studies revealed decreased expression of STAT3 and NF-kB in MR-treated cells.
- In vivo studies demonstrated a significant reduction in tumor volume and suppressed STAT3 expression in the MR group.
Conclusions:
- Methionine restriction effectively suppresses pancreatic cancer growth.
- The JAK2/STAT3 signaling pathway and NF-kB are key targets of MR in pancreatic cancer.
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