Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer

Abstract

The development of resistance to 5-fluorouracil (5FU) chemotherapy is a major handicap for sustained effective treatment in peritoneal carcinomatosis (PC) of colorectal cancer (CRC). Metabolic reprogramming of adipocytes, a component of the tumor microenvironment and the main composition of peritoneum, plays a significant role in drug resistance of PC, with the mechanisms being not fully understood. By performing metabolomics analysis, we identified glutamine (Gln), an important amino acid, inducing resistance to 5FU-triggered tumor suppression of CRC-PC through activating mTOR pathway. Noteworthily, genetic overexpression of glutamine synthetase (GS) in adipocytes increased chemoresistance to 5FU in vitro and in vivo while this effect was reversed by pharmacological blockage of GS. Next, we showed that methionine metabolism were enhanced in amino acid omitted from CRC-PC of GS transgenic (TgGS) mice, increasing intracellular levels of S-carboxymethy-L-cys. Moreover, loss of dimethylation at lysine 4 of histone H3 (H3k4me2) was found in adipocytes in vitro, which may lead to increased expression of GS. Furthermore, biochemical inhibition of lysine specific demethylase 1 (LSD1) restored H3k4me2, thereby reducing GS-induced chemoresistance to 5FU. Our findings indicate that GS upregulation-induced excessive of Gln in adipocytes via altered histone methylation is potential mediator of resistance to 5FU chemotherapy in patients with CRC-PC.

Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

“…The high expression of the methylated protein YTHDF1 promotes the high expression and activity of transglutaminase 1, resulting in CRC’s tolerance to cisplatin ( 177 ). The methylation of histone causes glutamine synthetase (GS) to be upregulated in adipocytes, and the resultant rise in the glutamine level is a potential resistance mechanism in patients with CRC to 5-FU ( 195 ). HIF-1α-induced glucose metabolism reprogramming confers 5-FU resistance to CRC cells ( 196 ).…”

“…synthetase (GS) to be upregulated in adipocytes, and the resultant rise in the glutamine level is a potential resistance mechanism in patients with CRC to 5-FU (195). HIF-1a-induced glucose metabolism reprogramming confers 5-FU resistance to CRC cells (196).…”

Targeting Oncometabolites in Peritoneal Cancers: Preclinical Insights and Therapeutic Strategies

“…Intercellular metabolic crosstalk underlying glutamine metabolism has been observed in the TME of multiple cancers. CAFs and adipocytes in the PTME can promote glutamine metabolism in cancer cells by synthesizing and releasing glutamine into the TME [ 71 , 72 ]. Specifically, CAFs stimulate glutamine metabolism in cancer cells by coupling the TCA cycle and glutamine synthesis and its subsequent release into the TME through multiple mechanisms.…”

“…This glutamine is taken up by the cancer cells through specific transporters and is converted into glutamate by glutaminases through glutaminolysis. Thus, glutamine is utilized by cancer cells to facilitate bioenergetic and biosynthetic pathways [ 72 ]. These observations highlight how the TME can dynamically modulate amino acid metabolism in peritoneal cancers.…”

“…Cancer cells override adipocytes for the uptake of glutamine from the PTME, and peritoneal adipocytes enhance endogenous glutamine synthesis to overcome the glutamine shortage. This process is mediated by the epigenetic de-repression of the gene GS, which encodes glutamine synthetase [ 72 ]. Increased glutamine levels in the peritoneal adipocytes lead to the release of glutamine to the PTME, replenishing the glutamine pool.…”