Osteopontin-a alters glucose homeostasis in anchorage-independent breast cancer cells

Abstract

Invasive breast tumor cells generate three splice variants of the metastasis gene osteopontin, while non-invasive breast cells express only the unspliced form or no osteopontin at all. One role for osteopontin in tumor progression is the support of anchorage-independence. Here we show that the full-length gene product, osteopontin-a, induces a gene expression profile that is associated with tissue remodeling and directed movement/sprouting. This occurs via signals through STAT1 and STAT3 to snglycero-3-phosphocholine. Osteopontin-a upregulates the levels of glucose in breast cancer cells, likely through STAT3 and its transcriptional targets apolipoprotein D and IGFBP5. The splice variants osteopontin-a and osteopontin-c may synergize, with each form activating signal transduction pathways that are distinct from the other. The elevated glucose is used by osteopontin-c dependent signals to generate chemical energy (Shi et al. manuscript submitted). The splice variant-specific metabolic effects of osteopontin add a novel aspect to the pro-metastatic functions of this molecule.

Metabolism in cancer metastasis

“…29 Surrounding stromal cells may facilitate the acquisition of a proinvasive metabolic profile. Under aerobic conditions, 15,16 Glucose utilization Glycolysis 1 Respiratory chain 17,18 Glutamine metabolism NADPH generation, oxaloacetate regeneration for the TCA cycle 10,11 Creatine synthesis for ATP regeneration 17 Peroxide Reduced production through mitochondrial hyperpolarization 9 Production essential for anchorage independence 17,[19][20][21][22] Outcome Biosynthesis 11 Overcome ATP deficit 18 to avoid anoikis 15 glycolysis is induced in mesenchymal stem cells adjacent to osteosarcoma cells. They then secrete lactate via the transporter MCT4.…”

“…Osteopontin-c is never expressed without the full-length form osteopontin-a, and the two variants may synergize in supporting the survival of circulating tumor cells. Osteopontin-a increases the glucose levels in deadherent breast tumor cells, 16 which may provide the biochemical fuel for osteopontin-c-dependent ATP generation. 17 The full-length protein, osteopontin-a, induces a gene expression profile that is associated with tissue remodeling and directed movement/sprouting 16 via signals through STAT3 50,51 to sn-glycero-3-phosphocholine.…”

“…Osteopontin-a increases the glucose levels in deadherent breast tumor cells, 16 which may provide the biochemical fuel for osteopontin-c-dependent ATP generation. 17 The full-length protein, osteopontin-a, induces a gene expression profile that is associated with tissue remodeling and directed movement/sprouting 16 via signals through STAT3 50,51 to sn-glycero-3-phosphocholine. It thus upregulates the levels of glucose in breast cancer cells, likely through the STAT3 transcriptional targets apolipoprotein D and IGFBP5.…”

“…It thus upregulates the levels of glucose in breast cancer cells, likely through the STAT3 transcriptional targets apolipoprotein D and IGFBP5. 16 When in solution, osteopontin-a has anti-apoptotic, prosurvival properties via engagement of its cognate receptors, 52 which may aid cancer progression. The elevated cellular glucose levels may supply the energy source for osteopontin-c-dependent anti-anoikis.…”

OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

“…In breast cancer cells, OPN‐a‐ but not OPN‐c‐transfected cells display signal transducer and activator of transcription 1 & 3 (STAT1/3) DNA binding (Shi et al . 2014). STAT1/3 activation occurs in response to cytokines, such as interleukin (IL)‐6, suggesting that OPN isoforms may differentially modulate inflammatory cytokine induction.…”