Glucose metabolic upregulation via phosphorylation of S6 ribosomal protein affects tumor progression in distal cholangiocarcinoma

Background: The prognosis of distal cholangiocarcinoma (dCCA) remains poor; thus, the identification of new therapeutic targets is warranted. Phosphorylated S6 ribosomal protein indicates a mammalian target of rapamycin complex 1 (mTORC1) activity, and mTORC1 plays a central role in controlling cell growth and regulating glucose metabolism. We aimed to clarify the effect of S6 phosphorylation on tumor progression and the glucose metabolic pathway in dCCA.

Methods: Thirty-nine patients with dCCA who underwent curative resection were enrolled in this study. S6 phosphorylation and the expression of GLUT1 were evaluated by immunohistochemistry, and their relationship with clinical factors was investigated. The effect of S6 phosphorylation on glucose metabolism with PF-04691502 treatment, an inhibitor of S6 phosphorylation, was examined in cancer cell lines by Western blotting and metabolomics analysis. Cell proliferation assays were performed with PF-04691502.

Results: S6 phosphorylation and the expression of GLUT1 were significantly higher in patients with an advanced pathological stage. Significant correlations between GLUT1 expression, S6 phosphorylation, and SUV-max of FDG-PET were shown. In addition, cell lines with high S6 phosphorylation levels showed high GLUT1 levels, and the inhibition of S6 phosphorylation reduced the expression of GLUT1 on Western blotting. Metabolic analysis revealed that inhibition of S6 phosphorylation suppressed pathways of glycolysis and the TCA cycle in cell lines, and then, cell proliferation was effectively reduced by PF-04691502.

Conclusion: Upregulation of glucose metabolism via phosphorylation of S6 ribosomal protein appeared to play a role in tumor progression in dCCA. mTORC1 may be a therapeutic target for dCCA.

 

Comments:

The study you described investigates the role of phosphorylated S6 ribosomal protein and its impact on tumor progression and glucose metabolism in distal cholangiocarcinoma (dCCA). Here's a breakdown of the key findings and conclusions from the study:

### Key Findings:

1. **Clinical Correlations:**
   - Patients with advanced pathological stages of dCCA exhibited significantly higher levels of S6 phosphorylation and GLUT1 expression.
   - Significant correlations were found between GLUT1 expression, S6 phosphorylation, and SUV-max (standardized uptake value-maximum) of FDG-PET (positron emission tomography with fluorodeoxyglucose).

2. **Cell Line Studies:**
   - Cell lines with elevated S6 phosphorylation levels also showed increased levels of GLUT1.
   - Inhibition of S6 phosphorylation using PF-04691502 led to a reduction in GLUT1 expression as observed in Western blotting.

3. **Metabolic Analysis:**
   - Metabolomics analysis indicated that inhibiting S6 phosphorylation suppressed glycolysis and the tricarboxylic acid (TCA) cycle pathways in cell lines.
   - This inhibition of glucose metabolism pathways was associated with reduced cell proliferation in the presence of PF-04691502.

### Conclusion:

The study concludes that the upregulation of glucose metabolism via phosphorylation of S6 ribosomal protein is implicated in the progression of dCCA. These findings suggest that the mammalian target of rapamycin complex 1 (mTORC1) could serve as a potential therapeutic target for dCCA. Inhibition of S6 phosphorylation using PF-04691502 was shown to be effective in suppressing glucose metabolism pathways, which, in turn, led to reduced cell proliferation.

These results highlight a potential avenue for targeted therapy in dCCA, focusing on disrupting the mTORC1 signaling pathway to impede tumor progression and alter glucose metabolism, which are critical factors in the aggressive nature of this cancer. Further research and clinical trials could explore the use of mTORC1 inhibitors as a promising strategy for treating distal cholangiocarcinoma.

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S2743	PF-04691502	PF-04691502 (PF4691502) is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. PF-04691502 induces apoptosis. Phase 2.

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Akt mTOR Apoptosis related PI3K