Visfatin-induced upregulation of lipogenesis via EGFR/AKT/GSK3β pathway promotes breast cancer cell growth

by Selleckchem | Jul 27 2023

Breast cancer (BC) incidence and associated mortality have increased in tandem with the growth in obesity among the females worldwide. An adipokine, visfatin, has been shown to potentially impact glucose, lipid, and protein metabolism, and promote cancer growth however, the mechanism underlying the effect of visfatin on lipid metabolism dysregulation contributing to BC cell survival, proliferation, and metastasis has not been elucidated. Herein, we have investigated the role of visfatin on the induction of Sterol regulatory element binding protein (SREBP-1) and its upstream and downstream mediators in MCF-7 breast cancer cells. The survival and proliferation was investigated using MTT and Trypan blue assays, cytosolic lipid accumulation was observed using Nile red staining, mRNA and protein expressions were examined using RT-qPCR and western blotting, respectively, and cell cycle analysis was performed using fluorescence-activated cell sorting. Our results indicate that visfatin increased the survival and proliferation of MCF-7 cells in a time- and dose-dependent manner and augmented lipid buildup via activation of SREBP-1 and its associated downstream lipid synthesizing enzymes, at both mRNA and protein levels in MCF-7 cells. Inhibiting SREBP-1 using fatostatin or silencing with siRNA abrogated excessive lipid deposition by suppressing the expression of genes related to lipid synthesis pathway. Further, in-silico study showed high affinity binding of visfatin with epidermal growth factor receptor (EGFR), which was confirmed in an in-vitro study where visfatin increased the phosphorylation of EGFR at tyrosine residue and activated its downstream proteins via phosphorylation of AKT and GSK3β in MCF-7 cells. Inhibition of GSK3β by phosphorylation led to increased activity of SREBP-1 and associated downstream proteins. In summary, SREBP-1 may be a critical player in visfatin-induced lipid synthesis and accumulation in BC cells via activation of EGFR/AKT/GSK3β pathway leading to increased cell survival and proliferation of BC cells.

Comments:

The paragraph you provided describes a study that investigated the role of the adipokine visfatin in breast cancer (BC) cell survival, proliferation, and lipid metabolism dysregulation. Here are the key findings and conclusions of the study:

1. Background: The incidence and mortality of breast cancer have increased alongside the global rise in obesity among females. Visfatin is an adipokine that has been implicated in glucose, lipid, and protein metabolism, as well as cancer growth.

2. Objective: The study aimed to understand the mechanism by which visfatin affects lipid metabolism dysregulation, leading to BC cell survival, proliferation, and metastasis.

3. Methodology: The researchers used MCF-7 breast cancer cells as a model and performed various assays and analyses to investigate the impact of visfatin on cell survival, proliferation, lipid accumulation, gene expression, and protein activation.

4. Results:
   a. Visfatin increased the survival and proliferation of MCF-7 cells in a time- and dose-dependent manner.
   b. Visfatin promoted lipid buildup in MCF-7 cells by activating Sterol regulatory element binding protein 1 (SREBP-1) and its associated downstream lipid synthesizing enzymes at the mRNA and protein levels.
   c. Inhibiting SREBP-1 using fatostatin or silencing it with siRNA reduced excessive lipid deposition by suppressing the expression of genes involved in the lipid synthesis pathway.
   d. In-silico (computer-based) analysis showed a high affinity binding of visfatin with the epidermal growth factor receptor (EGFR).
   e. In an in-vitro study, visfatin increased the phosphorylation of EGFR at a specific tyrosine residue and activated downstream proteins, including AKT and GSK3β, in MCF-7 cells.
   f. Inhibition of GSK3β by phosphorylation led to increased activity of SREBP-1 and associated downstream proteins.

5. Conclusion: The study suggests that SREBP-1 plays a critical role in visfatin-induced lipid synthesis and accumulation in breast cancer cells. This effect is mediated through the activation of the EGFR/AKT/GSK3β pathway, leading to increased cell survival and proliferation in breast cancer.

It is important to note that this paragraph represents a summary of the study you provided and should not be considered medical advice or a comprehensive analysis of the research.