Phosphoglucomutase 1 (PGM1) expression and regulation in cancer cells

Includes bibliographical referencesCancer cells undergo metabolism that is significantly different to normal cells, with an increased dependence on glucose metabolism as a hallmark of most cancers. Changes in global gene expression patterns are the major driving forces behind cancer progression. These changes trigger events that result in the dysregulation of key enzymes associated with metabolic processes. Gene expression profiling studies done previously in our laboratory identified a group of genes involved in glucose metabolism to be differentially expressed in cervical cancer patient material. Of these, Phosphoglucomutase 1 (PGM1) was identified to have elevated expression in the cancer group. PGM1 is a phosphotransferase that catalyses the reversible conversion of the glycogen breakdown product, glucose-1-phosphate into glucose-6-phosphate, a substrate for glycolysis and the pentose phosphate pathway. This places PGM1 at a critical traffic point of glucose metabolism. In this study we investigated the expression, regulation and biological significance of PGM1 in cancer cells. Our results showed that PGM1 expression was elevated in cervical cancer tissue compared to normal. Its expression was also high in cervical, oesophageal and breast cancer cell lines. Elevated PGM1 expression associated with high promoter activity as well as with E2F and HIF1α activities in cancer cells. PGM1 expression at the level of mRNA, protein and promoter activation was significantly stimulated in hypoxia mimicking conditions. Our data showed that PGM1 expression in cancer cells was required mainly for glycogen accumulation with marginal changes on glycolysis and the pentose phosphate pathway. While PGM1 expression did not appear necessary for cancer cell proliferation in normoxia and nutrient sufficiency, our data shows that it is required for proliferation under conditions of glucose deprivation combined with hypoxia. Together these findings suggest that PGM1 expression is altered in cancer cells, that it is required for aberrant glycogen expression in cancer cells and that it has a role in cancer biology during severe stress conditions

The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma

Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma