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Other Functions of HCA Receptors HCA receptors, in particular HCA1, are expressed in various primary tumor FK228 77, 78, 79. This is of interest, as most solid tumors show increased glucose uptake and lactate formation even under normoxic conditions, with lactate concentrations in the tumor microenvironment as high as 30mM [80], sufficient to activate HCA1. Several in vitro studies showed that inhibition or suppression of HCA1 activation can result in reduced survival of tumor cells. Various mechanisms have been proposed to explain reduced tumor cell survival after HCA1 inhibition including a lipogenic/lipolytic imbalance, which may affect proliferation of HER2 overexpressing cancer cells 77, 81, a reduced expression of the lactate transporter resulting in reduced uptake [79], or a reduced lactate-induced DNA repair [78]. Human pancreatic adenocarcinoma cells with silenced HCA1 expression showed significantly reduced tumor growth and metastasis in an in vivo xenograft model [79], and recent evidence suggests that activation of HCA1 on breast cancer cells also promotes tumor angiogenesis by stimulating the expression of the proangiogenic mediator amphiregulin [82]. There is also evidence that HCA2 and HCA3 can modulate tumor initiation and growth, but the underlying mechanisms are unclear 77, 83. Evidence for a role for HCA2 in the host–pathogen interaction came from a screen for genes encoding proteins that affect the intracellular load of human macrophages infected with Mycobacterium tuberculosis84, 85. The proposed model suggests that virulent M. tuberculosis taken up by human macrophages induces metabolic flux perturbations through the secreted protein ESAT-6, resulting in the formation of β-HB, which then in an autocrine or paracrine fashion acts on HCA2 receptors to reduce triglyceride turnover, thus leading to the accumulation of lipid bodies 84, 86, 87. The formation of lipid bodies in macrophages is regarded as a mechanism allowing stable persistence of M. tuberculosis. Whether blockade of HCA2 by antagonists is a strategy for chemotherapy of tuberculosis needs to be tested.
Therapeutic Potential The ketone body receptor HCA2 is already a well-established target for several drugs, including nicotinic acid and other antidyslipidemic/antiatherogenic compounds, as well as the monomethyl fumarate precursor DMF that is being used to treat psoriasis and relapsing multiple sclerosis 63, 88. The clinical efficacies of nicotinic acid and DMF have been described before, and HCA2 was recognized as a critical mediator of their effects. It therefore appears possible that the full potential of HCA2 as a drug target has not yet been exploited. Therefore, synthetic HCA2 agonists with improved agonistic properties or combinations of HCA2 agonists with other drugs that reduce unwanted effects resulting from HCA2 activation can be developed. For instance, in an attempt to reduce the unwanted flushing effect of nicotinic acid, extended release formulations combined with the prostaglandin D2 receptor (DP1) antagonist laropiprant, which suppresses part of the prostanoid-mediated flush response 89, 90, have been generated. Although the flushing effect was less pronounced with this new formulation, efficacy regarding the treatment and prevention of cardiovascular diseases appeared to be reduced 61, 62. Other approaches aimed at the generation of synthetic HCA2 receptor partial agonists, or compounds with signaling bias toward G protein-mediated signaling compared with β-arrestin-mediated signaling 4, 7 as evidence have indicated that the major unwanted effect mediated by HCA2 activation, the cutaneous flushing response, is mediated by β-arrestin rather than G proteins [91]. Whether any of these new synthetic HCA2 agonists are superior to nicotinic acid or DMF and other fumaric acid esters is not known. Activation of HCA2 receptors could be a therapeutic approach to treat various other inflammatory and immunological disorders in addition to atherosclerosis and multiple sclerosis. There is experimental evidence to support a beneficial role of HCA2 activation in colitis and intestinal allergy 72, 73, 74. Given that the precursor of the HCA2 agonist monomethyl fumarate, DMF, has a well-established efficacy in the treatment of psoriasis 68, 69 and since HCA2 is widely expressed in the epidermis [6], it is possible that psoriasis and presumably other skin diseases involving the epidermis respond to HCA2 activation.