Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

Abstract

Since bone metastatic breast cancer is an incurable disease, causing significant morb idity and mortality, understanding of the underlying molecu lar mechanisms would be h ighly valuable. Here, we describe in v itro and in v ivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Geno me -wide gene exp ression profiling of th is isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian t issues. Consistently, we observed that the proliferat ion of MDA -MB-231(SA) cells in serine-free conditions was dependent on PSAT1 exp ression. In addition, we observed that L-serine is essential for the fo rmation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell pro liferat ion indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.

Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation

“…There are three enzymes, 3-phospho-glycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH), which are required for the three-step conversion of the glycolytic intermediate 3-PG to serine. All three enzymes have previously been found to be overexpressed or demonstrate increased activity in tumor tissue (29)(30)(31)(32)(33)(34), suggesting this serine synthetic pathway may play an important role in tumorigenesis. To test this idea, we blocked this pathway by suppressing PSAT1 with RNAi.…”

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

“…MDA-MB-231(SA) cells were comprehensively characterized by comparative genomic hybridization and genomewide gene expression profiling by our research group as described in (6). The cells were cultured in Dulbecco's Modified Eagle's Medium supplemented with 10% inactivated calf serum, 1% penicillin/streptomycin, and nonessential amino acids at þ37 C in a humidified incubator in an atmosphere of 5% CO 2 .…”

“…RNA isolation, reverse transcription, and TaqMan analyses were done as previously described (6). The primers and probes are listed in the Supplementary Table S1.…”

The Phosphorylated Pathway of Serine Biosynthesis Is Essential Both for Male Gametophyte and Embryo Development and for Root Growth in Arabidopsis

“…In humans, the PPSB plays a crucial role in cell proliferation control. This pathway can divert a substantial fraction of the glycolytic flux (carbon metabolism) into Ser biosynthesis (nitrogen metabolism) and can contribute to cell proliferation and oncogenesis (Bachelor et al, 2011;Locasale et al, 2011;Pollari et al, 2011;Possemato et al, 2011). For instance, an enhanced PPSB results in an increased cell proliferation rate, which is associated with certain breast cancers (Locasale et al, 2011;Possemato et al, 2011).…”