It is widely accepted that changes in metabolism are linked to cellular transformation and tumor progression (Currie et al. 2013; Santos and Schulze 2012). While most of the focus in recent years has been on glucose and glutamine metabolism (Pavlova and Thompson 2016), abnormal choline metabolism is increasingly recognized as a critical aspect of the tumor metabolome (Aboagye and Bhujwalla 1999; Ackerstaff et al. 2003; Glunde et al. 2004).
Recently, the group of Kristine Glunde and colleagues from Johns Hopkins University School of Medicine in Baltimore published an interesting study on control factors of choline phospholipid metabolism (Cao et al. 2016). The authors silenced two glycerophosphodiesterase genes, GDPD5 (GDE2) and GDPD6 (EDI3; GPCPD1; GDE5) in breast cancer cell lines and compared the effect on metabolite levels and cellular processes. In an analysis of choline metabolite profiles, the authors demonstrated that knockdown of both GDPD5 and EDI3 led to increased levels of glycerophosphocholine (GPC). This is in agreement with previously published work showing that GPC is a major substrate for both enzymes, which they cleave to release choline and glycerol-3-phosphate (Gallazzini et al. 2008; Okazaki et al. 2010; Stewart et al. 2012). Furthermore, the findings by the Glunde group support previous data that demonstrated decreased cell migration after EDI3 silencing in MCF-7 and MDA-MB-231 breast cancer cell lines (Stewart et al. 2012). Importantly, the authors describe for the first time, a role for GDPD5 in this process (Cao et al. 2016).
EDI3 was recently shown to be a choline-releasing glycerophosphodiesterase that drives tumor cell migration, and is a key enzyme in choline and lipid metabolic pathways, as well as being associated with metastasis (Stewart et al. 2012; Marchan et al. 2012a, b). Subsequent work also showed that EDI3 links choline metabolism to integrin expression, cell adhesion and spreading (Lesjak et al. 2014). An exciting novel aspect of the study by the Glunde group is that comparable knockdown of both EDI3 and GDPD5 in breast cancer cell lines significantly increased GPC levels with phenotypic consequences (Cao et al. 2016). This observation questions the need for two enzymes that catalyze the same reaction, as a different role or specialization has not been fully elucidated. Currently, research in this field is hampered by the lack of reagents, such as antibodies with high specificity and sensitivity, and many open questions remain. For instance, what are the molecular mechanisms linking GDPD5 and EDI3 to the observed phenotypic changes, such as increased migration capacity, and are they different between the enzymes. From the study by Kristine Glunde’s group, EDI3 appears to have a stronger effect on GPC levels and there are differences in the extent to which both enzymes influence migration and invasion, as well as proliferation, where only GDPD5 appears to be relevant. This prompted the authors to speculate that combined inhibition of both enzymes may represent a potentially new targeting strategy in the treatment of breast cancer. However, of particular interest is whether the so far only in vitro studied migration and invasion phenotypes in cancer cell lines translates to an increased risk of metastasis or local tumor invasion in patients.
Metastasis and tumor progression are complex processes that include increased apoptosis resistance (Siddiqui et al. 2015; Petry et al. 2010), activation of inflammatory pathways (Mattsson et al. 2015), mutations (Suda and Mitsudomi 2015), altered miRNAs (Yanokura et al. 2015), as well as loss of control in signaling and cell proliferation (Kim and Choi 2015; Cadenas et al. 2014; Marchan 2014a, b). Although evidence for an association between choline metabolism and tumor progression has been published (e.g., Ackerstaff et al. 2001; Franks et al. 2002; Swanson et al. 2008), the situation is far from being understood. Studying only individual metabolites or enzymes in relation to clinical parameters may also lead to conflicting results, because the activity of an entire pathway may be more relevant and should be taken into account. In conclusion, choline metabolism represents an emerging field in cancer research. However, the search for the mechanisms how increased cleavage of GPC is linked to increased tumor cell migration and eventually worse prognosis has only just begun.
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Marchan, R. GDPD5, a choline-generating enzyme and its novel role in tumor cell migration. Arch Toxicol 90, 3143–3144 (2016). https://doi.org/10.1007/s00204-016-1847-z
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DOI: https://doi.org/10.1007/s00204-016-1847-z