Abstract
Related research has recognized the vital role of methionine cycle metabolism in cancers. However, the role and mechanism of methionine cycle metabolism in hepatocellular carcinoma are still unknown. In this study, we found that [Cu(ttpy-tpp)Br2]Br (Referred to as CTB) could induce hepatocellular carcinoma cells senescence, which is a new copper complex synthesized by our research group. Interestingly, CTB induces senescence by inhibiting the methionine cycle metabolism of HCC cells. Furthermore, the inhibitory effect of CTB on the methionine cycle depends on mitochondrial carrier protein SLC25A26, which was also required for CTB-induced HCC cells senescence. Importantly, we found that CTB-induced upregulation of SLC25A26 could cause abnormal methylation of TERT and inhibited TERT expression, which is considered to be an essential cause of cell senescence. The same results were also obtained in vivo, CTB inhibits the growth of subcutaneously implanted tumors in nude mice and promoted the expression of senescence markers in tumor tissues, and interference with SLC25A26 partially offset the antitumor effect of CTB.
Highlights
Hepatocellular carcinoma (HCC) is one of the malignant tumors with high mortality, and it lacks effective treatment[1,2]
We further examined the effect of CTB on the rate-limiting enzyme MAT2A of methionine cycle metabolism
The results showed that siSLC25A26 treatment canceled the inhibitory effect of CTB on HCC cells methionine cycle, which were confirmed after analyzing of methionine cycle metabolism rate-limiting enzyme MAT2A by western blot and real-time PCR (Fig. 5D, E)
Summary
Hepatocellular carcinoma (HCC) is one of the malignant tumors with high mortality, and it lacks effective treatment[1,2]. Infinite proliferation is a crucial characteristic of tumor cells[7], and senescence becomes an effective way to inhibit malignant transformation by limiting the cell’s replication lifespan[8]. We often directly induce tumor cells apoptosis or other death methods, and these strategies or drugs strongly suppress the malignant proliferation of tumor cells. These methods often cause extremely serious toxic and side effects due to the lack of drugs that completely target tumor cells. It may be an important anti-tumor strategy that inducing tumor cells to senescent state, and targeting these senescent cells
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