New Mechanism of Metformin For Controlling Lipogenesis And Inhibiting The Growth of Cancer Cells

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New Mechanism of Metformin For Controlling Lipogenesis And Inhibiting The Growth of Cancer Cells Metformin lowers blood sugar by inhibiting the production of glucose in the liver. It is the first-line drug for type 2 diabetes and one of the most commonly prescribed drugs in the world. There are hundreds of millions of people taking metformin worldwide.

As an old drug, researches on metformin have never stopped, and the research enthusiasm is also increasing. Metformin always refreshes our understanding of it, and continues to bring people one surprise after another.

In recent years, many studies have shown that metformin has the effect of weight loss in addition to its hypoglycemic effect. Many preclinical and clinical studies have also observed that metformin has beneficial effects in anti-aging, treatment of cognitive impairment, cancer, and cardiovascular diseases.

On March 1, 2021, the team of Xiaoping Yang from Hunan Normal University published an online research paper titled: Metformin targets Clusterin to control lipogenesis and inhibit the growth of bladder cancer cells through SREBP-1c/FASN axis in the Journal of Signal Transduction and Targeted Therapy.

The study confirmed that Clusterin is the target of metformin and metformin inactivates SREBP-1c and its downstream FASN by targeting Clusterin, which results in the hindrance of fatty acid synthesis and thus inhibits the growth of bladder cancer.

This study provides a new potential method for the personalized treatment of metformin through the differential analysis of protein expression in cancer patients.

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Previous studies have shown that metformin has anti-cancer properties, but the clinical trials that have been initiated have not achieved satisfactory results. This may be because the current anti-cancer mechanism of metformin and its exact therapeutic target are still unclear.

In order to identify the potential therapeutic targets of metformin in bladder cancer, the research team used high-throughput protein chips to screen different proteins for metformin treatment in bladder cancer cells. The screening results showed that clusterin is the target of metformin and metformin can directly bind to it. Metformin therapy will also significantly reduce the expression level of clusterin in bladder cancer cells.

Clusterin, also known as TRPM-2, is a secreted heterodimeric glycoprotein that is highly expressed in a variety of malignant tumor cells, so it is considered a potential cancer treatment target.

In order to determine the direct role of clusterin in the growth of bladder cancer cells, the research team used siRNA and RNAi lentivirus to knock down the expression level of clusterin in bladder cancer cells.

The test results show that knocking down the expression level of Clusterin can significantly inhibit the viability, migration, clone formation, and induce apoptosis of bladder cancer cells. Overexpression of Clusterin will increase the clonal formation, proliferation and migration of bladder cancer cells. These experimental results show that Clusterin plays a role in promoting cancer of the bladder cancer.

Next, the research team studied the effects of metformin on bladder cancer cells with different expression levels of Clusterin.

The results showed that metformin could significantly inhibit the proliferation and migration of bladder cancer cells, but the inhibition effect of metformin on bladder cancer cells with

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high expression level of Clusterin was better, and the inhibition effect of metformin on bladder cancer cells with low expression level of Clusterin was decreased.

These results suggested that metformin could inhibit the bladder cancer cells, but the bladder cancer cells with high expression of Clusterin were more sensitive to metformin.

Since Clusterin is involved in lipid transport and metabolism, and metformin has a good effect on weight loss, the research team then further investigated whether Clusterin plays a role in metformin's inhibition of fat production.

In previous studies, the research team found that metformin reduced the expression of FASN in bladder cancer cells. FASN and SREBP-1c were significantly increased in bladder cancer cell lines and tissues, both of which are related to fat metabolism.

The research team found that knocking down the expression level of Clusterin inhibits the transcriptional activity of SREBP-1c and inhibits adipogenesis. These results confirmed the inhibition of fat formation by inhibiting the expression level of Clusterin.

Next, the research team conducted experiments in mice, and the results showed that bladder cancer cells that knocked down the expression of Clusterin formed smaller tumors after subcutaneous transplantation. This indicates that inhibiting the expression of Clusterin can effectively inhibit the proliferation of bladder cancer cells in vivo. In addition, bladder cancer cells that knocked down Clusterin also reduced the protein levels of FASN and SREBP-1c.

Considering the potent inhibitory effect of metformin on the growth of bladder cancer cells, the research team evaluated the anti-tumor effect of metformin in a mouse model.

The results showed that metformin significantly reduced the growth rate of bladder cancer cells in mice.

In addition, mice treated with metformin showed lower adipogenesis. At the same time, the research team also found that metformin reduced the expression levels of Clusterin, SREBP-1c and FASN.

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The above results prove that metformin can block the growth of bladder cancer cells in the body and inhibit proteins related to fat formation.

Finally, the research team compared the TCGA database and clinical samples and found that the expression level of clusterin was positively correlated with the progression of bladder cancer.

In general, this study confirmed that Clusterin is the target of metformin. Metformin inactivates SREBP-1c and its downstream FASN by targeting Clusterin, which results in the hindrance of fatty acid synthesis and thus inhibition bladder cancer grows.

These results reveal the important role of clusterin-regulated adipogenesis in maintaining the growth and survival of bladder cancer. This study provides a new potential method for the personalized treatment of metformin through the differential analysis of protein expression in cancer patients.

Huateng Pharma is a leading supplier of innovative chemistry products and services thro ughout the pharmaceutical R&D and commercial production. We provide a variety of APIs and pharmaceutical intermediates such as metformin with capacities varying from gram to kilograms and multi tons.

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Reference: Metformin targets Clusterin to control lipogenesis and inhibit the growth of bladder cancer cells through SREBP-1c/FASN axis Related articles: [1] Does Metformin Benefit The Risk And Survival Of Lung Cancer In T2DM Patients?

[2] New Discoveries Of Metformin [3] Diabetes Drug Metformin May Prevent Dementia