Long noncoding RNA OVAAL enhances nucleotide synthesis through pyruvate carboxylase to promote 5‐fluorouracil resistance in gastric cancer

Abstract

5‐Fluorouracil (5‐FU) is widely used in gastric cancer treatment, yet 5‐FU resistance remains an important clinical challenge. We established a model based on five long noncoding RNAs (lncRNA) to effectively assess the prognosis of gastric cancer patients; among them, lncRNA OVAAL was markedly upregulated in gastric cancer and associated with poor prognosis and 5‐FU resistance. In vitro and in vivo assays confirmed that OVAAL promoted proliferation and 5‐FU resistance of gastric cancer cells. Mechanistically, OVAAL bound with pyruvate carboxylase (PC) and stabilized PC from HSC70/CHIP‐mediated ubiquitination and degradation. OVAAL knockdown reduced intracellular levels of oxaloacetate and aspartate, and the subsequent pyrimidine synthesis, which could be rescued by PC overexpression. Moreover, OVAAL knockdown increased sensitivity to 5‐FU treatment, which could be reversed by PC overexpression or repletion of oxaloacetate, aspartate, or uridine. OVAAL overexpression enhanced pyrimidine synthesis to promote proliferation and 5‐FU resistance of gastric cancer cells, which could be abolished by PC knockdown. Thus, OVAAL promoted gastric cancer cell proliferation and induced 5‐FU resistance by enhancing pyrimidine biosynthesis to antagonize 5‐FU induced thymidylate synthase dysfunction. Targeting OVAAL‐mediated nucleotide metabolic reprograming would be a promising strategy to overcome chemoresistance in gastric cancer.

Long Non-Coding RNAs in Drug Resistance of Gastric Cancer: Complex Mechanisms and Potential Clinical Applications

“…But mainly, most lncRNAs related to drug resistance are transmitted from the nucleus to the cytoplasm to stabilize some important proteins in the cytoplasm. LncRNAs associated with drug resistance that function similarly include the following: ARHGAP5-AS1 [ 36 ], SNHG12 [ 94 ], OVAAL [ 152 ], and CBSLR [ 40 ]. By recruiting METTL3, ARHGAP5-AS1 stabilizes ARHGAP5 mRNA in the cytoplasm, thereby stimulating m6A modification of ARHGAP5 mRNA and upregulating the expression of the ARHGAP5 protein in drug-resistant cells [ 36 ].…”

“…SNHG12 can bind to HuR and form a “SNHG12-HuR” complex in the cytoplasm, thus increasing the relative HuR expression at the RNA and protein levels and enhancing the stability of YWHAZ mRNA, which promotes GC cell proliferation and chemoresistance [ 94 ]. In the cytoplasm, OVAAL can interact with PC (pyruvate carboxylase) and inhibit the ubiquitination of PC mediated by the complex formed by HSC70 and CHIP protein, thereby stabilizing the level of PC protein, which decreases sensitivity to 5-FU treatment [ 152 ]. CBSLR combines with YTHDF2 to form a compound that destroys the stability of CBS mRNA by increasing the binding of YTHDF2 with the m6A-modified coding sequence (CDS) of CBS mRNA, which keeps GC cells away from ferroptosis and contributes to chem-resistance in GC [ 40 ] ( Figure 2 B).…”

“…CRNDE in TAM-derived exosomes regulated PTEN expression by modulating NEDD4-1-mediated PTEN ubiquitylation, thus influencing the DDP resistance in GC [ 149 ]. OVAAL enhanced 5-FU resistance in GC by upregulating the levels of PC (pyruvate carboxylase) protein at the post-transcriptional level, thereby inhibiting the ubiquitin-mediated degradation of the PC protein [ 152 ]. In addition, the lncRNA CBSLR-YTHDF2 protein complex destabilized CBS mRNA by promoting the interaction between YTHDF2 and the m6A-modified CDS region of CBS mRNA, eventually leading to the high ubiquitination of the ACSL4 protein in GC cells [ 40 ] ( Figure 3 ).…”

“…OVAAL binds to PC and stabilizes PC against HSC70/CHIP-mediated cytoplasmic ubiquitination and degradation in the cytoplasm. The above process eventually triggers the production of oxaloacetate from pyruvate and the following accumulation of malate and aspartate, leading to 5-Fu resistance [ 152 ] ( Figure 5 ).…”