Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions, and Therapeutic Potential in Cancer

Abstract

The ketone bodies (KBs) β-hydroxybutyrate and acetoacetate are important alternative energy sources for glucose during nutrient deprivation. KBs synthesized by hepatic ketogenesis are catabolized to acetyl-CoA through ketolysis in extrahepatic tissues, followed by the tricarboxylic acid cycle and electron transport chain for ATP production. Ketogenesis and ketolysis are regulated by the key rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 2 and succinyl-CoA:3-oxoacid-CoA transferase, respectively. KBs participate in various cellular processes as signaling molecules. KBs bind to G protein-coupled receptors. The most abundant KB, β-hydroxybutyrate, regulates gene expression and other cellular functions by inducing post-translational modifications. KBs protect tissues by regulating inflammation and oxidative stress. Recently, interest in KBs has been increasing due to their potential for treatment of various diseases such as neurological and cardiovascular diseases and cancer. Cancer cells reprogram their metabolism to maintain rapid cell growth and proliferation. Dysregulation of KB metabolism also plays a role in tumorigenesis in various types of cancer. Targeting metabolic changes through dietary interventions, including fasting and ketogenic diets, has shown beneficial effects in cancer therapy. Here, we review current knowledge of the molecular mechanisms involved in the regulation of KB metabolism and cellular signaling functions, and the therapeutic potential of KBs and ketogenic diets in cancer.

Keywords: cancer; inflammation; ketogenic diet; ketone bodies; oxidative stress; post-translational modifications; β-hydroxybutyrate.

Figure 1

Ketogenesis and ketolysis pathways in mitochondria. Ketogenesis occurs predominantly in hepatic mitochondria using acetyl-CoA produced by β-oxidation of fatty acyl-CoA. After being taken up by extrahepatic tissues through monocarboxylic acid transporter (MCT), ketolysis occurs in the mitochondria, where β-hydroxybutyrate (BHB) and acetoactate (AcAc) are converted to Acetyl-CoA and ATP is produced via the tricarboxylic acid (TCA) cycle and electron transport chain (ETC).

Figure 2

Regulatory mechanisms for HMGCS2 and SCOT. 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) (A) and succinyl-CoA:3-oxoacid-CoA transferase (Oxct1/SCOT) (B) gene expressions are regulated at the transcriptional levels and their protein activities are regulated by the post-translational modifications. Arrow (→) and truncated line (┬) indicate activation and inhibition, respectively.

Figure 3

Signaling functions of ketone bodies for anti-inflammation, epigenetic and post-translational modifications, and antioxidative stress. Ketone bodies (KBs) including BHB exert a variety of beneficial effects. (A) KBs exhibit anti-inflammatory responses and modulate immune cell functions in a receptor (HCAR2)-dependent and independent manner. (B) KBs regulate various cellular processes by inducing epigenetic and post-translational modifications of histone and non-histone proteins and by reducing oxidative stress. Arrow (→) and truncated line (┬) indicate activation and inhibition, respectively.

Figure 4

Dysregulation of ketone body metabolism in cancer cells. (A) Changes in ketolysis in cancer cells. Many tumor cells are inefficient in KB utilization due to mitochondrial dysfunction and/or low ketolytic enzymes. (B) Changes in ketogenesis in cancer cells. Expressions of ketogenic enzymes and HCAR2 are altered in some cancer cell types. Blue () and red () arrows indicate increases and decreases, respectively.

Figure 5

Potential mechanisms for the beneficial effects of ketogenic diet and/or ketone bodies in cancer therapy. KDs exert anti-tumor effects through a variety of mechanisms, including elevated KB levels and decreased blood glucose. (A) KDs and/or KBs inhibit cancer cell proliferation and tumor growth. (B) KDs and/or KBs improve the tumor microenvironment and suppress cancer metastasis, cachexia, and sarcopenia. Arrow (→) and truncated line (┬) indicate activation and inhibition, respectively.