PRPS1 (Phosphoribosyl Pyrophosphate Synthetase 1)

It is a promising non-endocrine candidate for BC prevention. Future studies in immunocompetent BC prevention models are warranted.

EGF-activated CK2α phosphorylated CLOCK at S106, disrupting circadian rhythms and inducing CLOCK-dependent PRPS1/2 K29 acetylation to drive GBM progression. Clinically, CLOCK pS106, PRPS1/2 K29ac, and PRPS1/2 overexpression correlated with aggressive tumors and poorer prognosis, identifying an EGFR-CLOCK-PRPS1/2 oncogenic axis.

Treating TAMR cells with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented the efficacy of tamoxifen. Restoring ASS1 expression or inhibiting pyrimidine biosynthesis reinstated tamoxifen sensitivity. ASS1 could be a potential biomarker and therapeutic target in tamoxifen-resistant ILC patients, warranting further investigation.

Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.

Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer. NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.

Our study links nucleotide biosynthesis with RNA epigenetics in cancer progression through the PRPS2-MAT2A-WTAP/METTL3/METTL14 axis, and elucidates both enzyme-dependent and independent functions of PRPS2. These findings have significant implications for developing targeted therapies for cancers associated with PRPS2 abnormalities.

These findings emphasize the role of LOH in GC pathogenesis and underscore the need for further research to understand LOH-affected genes and their diagnostic or evolution potential in cancer management. Portions of this text were previously published as part of a preprint (https://www.medrxiv.org/content/10.1101/2024.07.29.24311063v1).

Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Restoring ASS1 expression or inhibiting pyrimidine biosynthesis restored tamoxifen sensitivity. ASS1 could be a potential biomarker and therapeutic target in tamoxifen resistant ILC patients, warranting further investigation.

Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.

LicA targets SREBP1, a central regulator of lipogenesis and immune response, reducing pro-tumorigenic aberrations in lipid homeostasis and inflammation. It is a promising non-endocrine candidate for BC prevention.

Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. De novo purine synthesis was selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.

Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.