Application Note
Cancer metabolic flexibility is linked to metastatic potential
A
lterations in cellular metabolism are a crucial hallmark of cancer, char- acterised by a metabolic shift from mitochondrial respiration (OXPHOS) to glycolysis as the source of cellular energy. Even in the presence of oxygen, tumour cells produce free protons (ie lactate production from glucose) at a higher rate than normal cells, often referred to as the Warburg effect. As a consequence, the microenvironment of solid tumours is acidic, which in turn signif- icantly affects tumour growth and local invasion. Specifically, low extracellular pH leads to increased release of proteolytic enzymes that result in degradation of the extracellular matrix.
Metabolic shift and tumour microenvi- ronment were studied and discussed in a series of papers herein. The cancer cells used in this analysis include several differ- ent cancer cell lines: 1) primary melanoma cells and cell lines; 2) PC3M, a prostate cell line, best described as a late stage tumour; and 3) SH-SY5Y, a neuroblastoma cell line, derived from a primary tumour. In the progression from normal human epidermal melanocytes to malignant melanomas, the metabolic shift from OXPHOS to glycolysis was revealed by Ho et al1 by elevated LDH enzymes. The switch to glycolysis in advanced melanoma cells is due to their central hypoxic state. However, lactate produced by glycolysis in the central hypoxic areas
fuels ATP production via
OXPHOS in the mitochondria in the nor- moxic regions. Ho et al1 found that enzymes associated with OXPHOS were also elevat- ed in primary and metastatic melanomas,
type for prostate cancer PC3M was gly- colytic relative to normal PC3. PC3M sig- nificantly increased glycolytic capacity with added glucose (following inhibition of mitochondrial ATP production), suggesting that PC3M have an enhanced capacity to rely on glycolysis to meet energy needs, rel- ative to PC3. The glycolytic metabolism of PC3M resulted in local acidosis, which supports rapid destruction of the normal stromal cells surrounding the tumour site, invasion and metastasis. However, lysine treatment neutralised the acidic conditions, disrupting tumorigenesis and prolonging cell survival.
Figure 1: Ratio of basal oxygen consumption rates (OCRs) and extracellular acidification rates (ECARs) in human epidermal melanocytes (HEM), melanoma cell lines and single-cell melanoma suspensions (ratio serves as an indicator of OXPHOS phenotype)
and that a substantial proportion of energy is actually derived from OXPHOS in melanoma tumours, while HEMs have lower OXPHOS and higher glycolysis (Figure 1). Results suggest that the progres- sion to advanced melanoma also correlated with increased metabolic flexibility. Using prostate cancer cells, PC3M, Ibrahim-Hashim et al2 demonstrated that PC3M were more metabolically active than normal prostate cell line (PCS) in vitro, for both OXPHOS (Figure 2A) and extracellu- lar acidification rates (Figure 2B). Similar to malignant melanoma cells, these results suggest increased metabolic flexibility with cancer progression. Also, like malignant melanoma cells, the basal metabolic pheno-
For PC3M prostate cancer cells, glucose availability increased ECAR and decreased OCR (Figure 2). This reciprocal relation- ship has also been observed in the SH- SY5Y neuroblastoma cell line, under con- ditions of fixed energy demand (Figure 3). The authors of this study3 also showed that reduced acidification affect proteins that associate with energy sensing and response pathways. ERK phosphorylation, EIRT1, and HIF1a decreased while AKT, p38 and AMPK phosphorylation increased. That is, restricting glycolytic flux increased mito- chondrial respiration.
DDW
References 1 Ho, J et al. Molecular Cancer 2012.
http://www.molecular-
cancer.com/content/11/1/76. 2 Ibrahim-Hashim, A et al. J. Cancer Sci. Ther. 2011. http://
dx.doi.org/10.4172/1948-5956,S1-004. 3 Swerdlow, RH et al. Biochim. Biophys. Acta 2013.
http://dx.doi.org/10.1016/j.bbagen. 2013.01.002.
Figure 2: Basal OCRs and ECARs were determined for PC3M and PCS cells in the presence or absence of 2g/L D-glucose
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Figure 3: OCR and ECAR values under the different glucose concentrations
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