HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation

Abstract

Energy metabolism reprogramming is becoming an increasingly important hallmark of cancer. Specifically, cancers tend to undergo metabolic reprogramming to upregulate a cell-dependent glutamine (Gln) metabolism. Notably, hepatocellular cell adhesion molecule (HepaCAM) has been previously reported to serve a key role as a tumour suppressor. However, the possible regulatory role of HepaCAM in Gln metabolism in prostate cancer (PCa) remains poorly understood. In the present study, bioinformatics analysis predicted a significant negative correlation among the expression of HepaCAM, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), glutaminase (GLS) and solute carrier family 1 member 5 (SLC1A5), components of Gln metabolism, in clinical and genomic datasets. Immunohistochemistry results verified a negative correlation between HepaCAM and PIK3CA expression in PCa tissues. Subsequently, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) assays were performed, and the results revealed markedly reduced levels of Gln and metabolic flux in the blood samples of patients with PCa and in PCa cells. Mechanistically, overexpression of HepaCAM inhibited Gln metabolism and proliferation by regulating PIK3CA in PCa cells. In addition, Gln metabolism was discovered to be stress-resistant in PCa cells, since the expression levels of GLS and SLC1A5 remained high for a period of time after Gln starvation. However, overexpression of HepaCAM reversed this resistance to some extent. Additionally, alpelisib, a specific inhibitor of PIK3CA, effectively potentiated the inhibitory effects of HepaCAM overexpression on Gln metabolism and cell proliferation through mass spectrometry and CCK-8 experiments. In addition, the inhibitory effect of PIK3CA on the growth of tumor tissue in nude mice was also confirmed by immunohistochemistry in vivo. To conclude, the results from the present study revealed an abnormal Gln metabolic profile in the blood samples of patients with PCa, suggesting that it can be applied as a clinical diagnostic tool for PCa. Additionally, a key role of the HepaCAM/PIK3CA axis in regulating Gln metabolism, cell proliferation and tumour growth was identified. The combination of alpelisib treatment with the upregulation of HepaCAM expression may serve as a novel method for treating patients with PCa.

Molecular and metabolic alterations of 2,3-dihydroquinazolin-4(1H)-one derivatives in prostate cancer cell lines

“…Arginine also regulates different aspects of tumorigenesis such as inflammation, cell growth and the synthesis of proline, polyamines and proteins 54,55 . Glutamine metabolism is highly upregulated by different oncogenic signals and is associated with the progression, survival and growth of PC [56][57][58] , while arginine is overexpressed in many tumors including PC 59 . Herein, C5 significantly decreased the level of both amino acids which might contribute to its potent cytotoxic effect in DU145 cells.…”

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

“…GLS1 has two splicing isoforms, kidney-type glutaminase (KGA) and the more active isoform glutaminase C (GAC) [ 185 ]. Increases in amino acid transporter expressions often coincide with increases to these other glutaminolytic enzymes [ 157 , 175 , 186 , 187 , 188 , 189 ]. More specifically, the overexpression of GLS for the first-step conversion of glutamine to glutamate in PCa cells can be MYC-driven and is associated with the maintenance of a cellular redox state that confers radioresistance [ 190 ].…”