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Published on: July 21, 2018
SIRT1 mediated gastric cancer progression under glucose deprivation through the FoxO1-Rab7-autophagy axis
Mengke Zhu1, Chao Wei2, Haijiang Wang1
1Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Purpose:
Silent mating type information regulator 2 homolog 1 (SIRT1) and autophagy have a two-way action (promoting cell death or survival) on the progression and treatment of gastric cancer (GC) under different conditions or environments. This study aimed to investigate the effects and underlying mechanism of SIRT1 on autophagy and the malignant biological behavior of GC cells under conditions of glucose deprivation (GD).
Materials And Methods:
Human immortalized gastric mucosal cell GES-1 and GC cell lines SGC-7901, BGC-823, MKN-45 and MKN-28 were utilized. A sugar-free or low-sugar (glucose concentration, 2.5 mmol/L) DMEM medium was used to simulate GD. Additionally, CCK8, colony formation, scratches, transwell, siRNA interference, mRFP-GFP-LC3 adenovirus infection, flow cytometry and western blot assays were performed to investigate the role of SIRT1 in autophagy and malignant biological behaviors (proliferation, migration, invasion, apoptosis and cell cycle) of GC under GD and the underlying mechanism.
Results:
SGC-7901 cells had the longest tolerance time to GD culture conditions, which had the highest expression of SIRT1 protein and the level of basal autophagy. With the extension of GD time, the autophagy activity in SGC-7901 cells also increased. Under GD conditions, we found a close relationship between SIRT1, FoxO1 and Rab7 in SGC-7901 cells. SIRT1 regulated the activity of FoxO1 and upregulated the expression of Rab7 through deacetylation, which ultimately affected autophagy in GC cells. In addition, changing the expression of FoxO1 provided feedback on the expression of SIRT1 in the cell. Reducing SIRT1, FoxO1 or Rab7 expression significantly inhibited the autophagy levels of GC cells under GD conditions, decreased the tolerance of GC cells to GD, enhanced the inhibition of GD in GC cell proliferation, migration and invasion and increased apoptosis induced by GD.
Conclusion:
The SIRT1-FoxO1-Rab7 pathway is crucial for the autophagy and malignant biological behaviors of GC cells under GD conditions, which could be a new target for the treatment of GC.
Insights
Silent mating type information regulator 1 (SIRT1) influences gastric cancer cell autophagy and survival under glucose deprivation. The SIRT1-FoxO1-Rab7 pathway is key, offering a potential new therapeutic target for gastric cancer treatment.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Silent mating type information regulator 1 (SIRT1) plays a dual role in gastric cancer (GC) progression and treatment.
- Autophagy is a cellular process with context-dependent effects on cancer cell survival and death.
Purpose of the Study:
- To investigate the role of SIRT1 in regulating autophagy in gastric cancer cells under glucose deprivation (GD).
- To elucidate the underlying molecular mechanisms by which SIRT1 affects malignant behaviors of GC cells during GD.
Main Methods:
- Utilized human gastric mucosal GES-1 cells and GC cell lines (SGC-7901, BGC-823, MKN-45, MKN-28).
- Simulated GD using low-glucose DMEM. Assessed cell proliferation, migration, invasion, apoptosis, cell cycle, and autophagy.
- Employed CCK8, colony formation, scratch, Transwell assays, siRNA interference, mRFP-GFP-LC3 adenovirus infection, flow cytometry, and western blot.
Main Results:
- SGC-7901 cells exhibited higher SIRT1 expression and basal autophagy, with increased autophagy activity under prolonged GD.
- Identified a SIRT1-FoxO1-Rab7 pathway where SIRT1 deacetylates FoxO1, upregulating Rab7 and influencing autophagy.
- Knockdown of SIRT1, FoxO1, or Rab7 reduced autophagy, decreased GD tolerance, inhibited proliferation, migration, and invasion, and increased GD-induced apoptosis in GC cells.
Conclusions:
- The SIRT1-FoxO1-Rab7 pathway is critical for regulating autophagy and malignant behaviors of gastric cancer cells under glucose deprivation.
- This pathway represents a promising novel therapeutic target for gastric cancer treatment.
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