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Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer.
Onco Targets Ther. 2020; 13:4833-4842.OT

Abstract

Background

Serine provides important precursors of protein, lipid, and nucleotide synthesis needed for tumor cell growth. Phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in the serine de novo synthesis pathway, is highly expressed in many tumor types (including gastric cancer) and negatively correlated with overall survival. Cisplatin is a chemotherapeutic drug commonly used in the treatment of gastric cancer. In this study, we mainly investigated the relationship between serine metabolism and resistance to cisplatin in gastric cancer cells, as well as the regulatory mechanism involved in this process.

Materials and Methods

We determined the effect of different concentrations of serine or a PHGDH inhibitor combined with cisplatin or oxaliplatin on the viability and apoptosis of SGC7901, BGC823, and MGC803 cells via the Cell Counting Kit-8 and Hoechst 33258 staining, respectively. Western blotting was utilized to detect the relative protein expression. Furthermore, we investigated DNA damage through the micrococcal nuclease sensitivity assay detected using agarose gels.

Results

We found that reduced concentrations of serine or inhibition of PHGDH hindered the toxicity and pro-apoptotic effects of cisplatin on gastric cancer cells. Moreover, the addition of serine could reverse the sensitivity of gastric cancer cells to cisplatin. Moreover, we found that DNA damage was reduced by treatment with PHGDH inhibitor NCT-503 or CBR-5884. Inhibition of serine metabolism induced a decrease in H3K4 tri-methylation, which was reversed by JIB-04 (inhibitor of H3K4 demethylase). The tolerance of gastric cancer cells to cisplatin was relieved by JIB-04. Through micrococcal nuclease experiments, we further found that inhibiting the activity of PHGDH strengthened chromatin tightness.

Conclusion

Inhibition of serine metabolism reduced H3K4 tri-methylation and increased the density of chromatin, which leads to decreased toxicity and pro-apoptotic effect of platinum chemotherapeutic drugs on gastric cancer cells.

Authors+Show Affiliations

Central Laboratory, Jinhua Hospital of Zhejiang University, Jinhua 321000, Zhejiang Province, People's Republic of China. Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310000, Zhejiang Province, People's Republic of China.Department of Medical Oncology, Jinhua Hospital of Zhejiang University, Jinhua 321000, Zhejiang Province, People's Republic of China.Department of Medical Oncology, Jinhua Hospital of Zhejiang University, Jinhua 321000, Zhejiang Province, People's Republic of China.Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310000, Zhejiang Province, People's Republic of China.Central Laboratory, Jinhua Hospital of Zhejiang University, Jinhua 321000, Zhejiang Province, People's Republic of China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32581546

Citation

Zhao, Xiaoya, et al. "Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer." OncoTargets and Therapy, vol. 13, 2020, pp. 4833-4842.
Zhao X, Fu J, Tang W, et al. Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer. Onco Targets Ther. 2020;13:4833-4842.
Zhao, X., Fu, J., Tang, W., Yu, L., & Xu, W. (2020). Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer. OncoTargets and Therapy, 13, 4833-4842. https://doi.org/10.2147/OTT.S246430
Zhao X, et al. Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer. Onco Targets Ther. 2020;13:4833-4842. PubMed PMID: 32581546.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer. AU - Zhao,Xiaoya, AU - Fu,Jianfei, AU - Tang,Wanfen, AU - Yu,Liangliang, AU - Xu,Wenxia, Y1 - 2020/05/29/ PY - 2020/6/26/entrez PY - 2020/6/26/pubmed PY - 2020/6/26/medline KW - DNA damage KW - PHGDH KW - cisplatin resistance KW - gastric cancer KW - serine metabolism SP - 4833 EP - 4842 JF - OncoTargets and therapy JO - Onco Targets Ther VL - 13 N2 - Background: Serine provides important precursors of protein, lipid, and nucleotide synthesis needed for tumor cell growth. Phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in the serine de novo synthesis pathway, is highly expressed in many tumor types (including gastric cancer) and negatively correlated with overall survival. Cisplatin is a chemotherapeutic drug commonly used in the treatment of gastric cancer. In this study, we mainly investigated the relationship between serine metabolism and resistance to cisplatin in gastric cancer cells, as well as the regulatory mechanism involved in this process. Materials and Methods: We determined the effect of different concentrations of serine or a PHGDH inhibitor combined with cisplatin or oxaliplatin on the viability and apoptosis of SGC7901, BGC823, and MGC803 cells via the Cell Counting Kit-8 and Hoechst 33258 staining, respectively. Western blotting was utilized to detect the relative protein expression. Furthermore, we investigated DNA damage through the micrococcal nuclease sensitivity assay detected using agarose gels. Results: We found that reduced concentrations of serine or inhibition of PHGDH hindered the toxicity and pro-apoptotic effects of cisplatin on gastric cancer cells. Moreover, the addition of serine could reverse the sensitivity of gastric cancer cells to cisplatin. Moreover, we found that DNA damage was reduced by treatment with PHGDH inhibitor NCT-503 or CBR-5884. Inhibition of serine metabolism induced a decrease in H3K4 tri-methylation, which was reversed by JIB-04 (inhibitor of H3K4 demethylase). The tolerance of gastric cancer cells to cisplatin was relieved by JIB-04. Through micrococcal nuclease experiments, we further found that inhibiting the activity of PHGDH strengthened chromatin tightness. Conclusion: Inhibition of serine metabolism reduced H3K4 tri-methylation and increased the density of chromatin, which leads to decreased toxicity and pro-apoptotic effect of platinum chemotherapeutic drugs on gastric cancer cells. SN - 1178-6930 UR - https://www.unboundmedicine.com/medline/citation/32581546/Inhibition_of_Serine_Metabolism_Promotes_Resistance_to_Cisplatin_in_Gastric_Cancer L2 - https://dx.doi.org/10.2147/OTT.S246430 DB - PRIME DP - Unbound Medicine ER -
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