September 28, 2017 – One of the ways the body controls the overall number of cells is by initiating a preprogrammed cell death routine, known as apoptosis, in damaged or otherwise unnecessary cells. Apoptosis allows elimination of cells without induction of an autoimmune response. A hallmark of many types of cancer cells is a resistance to apoptosis; hence, tumors continue to grow and metastasize. Finding ways to defeat this resistance in cancer cells is an area of active research.

What they did:
The protein p53 is a major regulator of apoptosis, and is often mutated in cancer. At the NRI, the Krupenko laboratories previously determined that low-folate stress could induce apoptosis in cancer cells, and that this effect required functional (non-mutated) p53 and involved increased production of a type of molecule known as ceramide (Hoeferlin et al., 2013). New research published last year (Fekry et al., 2016) now provides details as to how this process takes place. They found that low folate activates p53, activated p53 enhances transcription of the CerS6 gene, and increased CerS6 causes increased production of ceramides, ultimately resulting in apoptosis. These results highlight how nutrient levels can influence cell growth, replication, and death.

Why it matters:
To take maximum translational advantage of an initial basic science discovery (e.g., low-folate stress results in increased production of ceramide), it is helpful to understand how and why it works. The Krupenko laboratories have already shown that excess dietary folate can worsen tumor growth and metastasis (Oleinik et al., 2014). But while knowing that dietary folate can worsen cancer metastasis would suggest lowering folate intake for cancer patients, we also know that folate plays multiple roles and remains an essential nutrient. By identifying how low folate can enhance our natural anti-cancer response (in this case, p53-mediated activation of CerS6), we gain new therapeutic targets that could possibly be exploited in future drug development efforts.

CerS6 Is a novel transcriptional target of p53 protein activated by non-genotoxic stress.
Fekry B, Jeffries KA, Esmaeilniakooshkghazi A, Ogretmen B, Krupenko SA, Krupenko NI (2016). J Biol Chem, 291:16586-16596

Folate stress induces apoptosis via p53-dependent de novo ceramide synthesis and up-regulation of ceramide synthase 6.
Hoeferlin LA, Fekry B, Ogretmen B, Krupenko SA, Krupenko NI (2013). J Biol Chem, 288:12880-12890.

Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation.
Oleinik NV, Helke KL, Kistner-Griffin E, Krupenko NI, Krupenko SA (2014). J Biol Chem, 289:26383-26394.