Review: Ketogenic diet in the treatment of cancer – Where do we stand? 評論：生酮飲食治療癌症-我們的立場是什麼？

4.4. Ketone bodies as signaling molecules

Extensive information concerning the molecular targets of ketone bodies comes from studies in brain malignancies and brain injury models. The obtained results are in general discussed with regard to the anti-seizure activity of ketones. However, some of the potential targets and mechanisms might explain the mode of action of the KD in tumor therapy. In addition, the downstream products of BHB metabolism, including acetyl-CoA, succinyl-CoA, and nicotinamide adenine dinucleotide, have signaling activities [132].

Modulation of N-methyl-d-aspartate (NMDA) signaling by BHB has been shown in several studies [133], [134]. The ketone bodies acetone and BHB inhibit the function of specific NMDA receptors in Xenopus oocytes. Acetone enhances, while BHB inhibits, α1 glycine and α1β2γ2S GABAA receptor function at physiologically relevant concentrations [135]. NMDA receptor expression has been observed in various types of cancer, along with other glutamate receptors, but functional validation has largely been limited to demonstrating the effect of receptor blockade on cell survival [136].

Hydroxy-carboxylic acid receptor 2 (HCA2) is a G protein-coupled receptor that is activated by BHB. HCA2 can activate specific macrophages, which have neuroprotective effects [137]. Activation of retinal HCA2 by systemic BHB inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome [138]. Interestingly, HCA2 was described as a tumor suppressor. Decreased synthesis of BHB suppresses signaling via the HCA2 receptor. Therefore, low levels of BHB attenuate the tumor-suppressing function of HCA2 in colon [139]. Recent studies have extended the tumor-suppressive function of the receptor beyond the colon, as HCA2 suppresses mammary tumorigenesis in a mouse model of breast cancer [140].

Mitochondrial membrane potential depends on several factors, an important one being the balanced presence of anti-apoptotic Bcl-2 and Bcl-xl and pro-apoptotic Bad and Bax proteins. Phosphorylation of Bad at Ser112 and Ser136 promotes its binding to 14-3-3 proteins, sequestering Bad away from the mitochondrial membrane [141]. A KD increased the phosphorylation of Bad Ser136 and the interaction between Bad and 14-3-3, actions which may underlie the diet’s neuroprotective properties against kainic acid-induced status epilepticus [142]. In the early 1970s, Kerr et al. linked apoptosis to the elimination of malignant cells, hyperplasia and tumor progression [143], [144]. Furthermore, reduced apoptosis or its resistance plays a fundamental role in carcinogenesis.

In contrast to the antitumor effects of ketone bodies described so far, it has been reported that ketone bodies can behave as onco-metabolites and that enzymes involved in ketogenesis or ketolysis are metabolic oncogenes. This was shown in vivo and in vitro using breast cancer xenografts and co-cultures of breast cancer cell lines and immortalized fibroblasts [145]. Moreover, the ketogenic enzyme HMG-CoA lyase is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukemia cells. Active BRAF upregulates the HMG-CoA product AcAc, which selectively enhances binding of BRAF V600E but not BRAF wild-type to MEK1 to promote activation of MEK-ERK signaling to stimulate tumor growth [67], [146].