Cancer as a Metabolic Disorder

Abstract

Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.

Keywords: cancer; fatty acids; glucose; glutamine; metabolism.

Figure 1

Nuclear–cytoplasmic studies (modified from the nucleus and mitochondria in the origin of tumors as previously described by Seyfried, 2012d; Seyfried et al., 2014). These studies involved the replacement of damaged mitochondria with normal mitochondria or the replacement of the nucleus of a cancerous cell with a normal cell nucleus. If cancer originates from a damaged nucleus, replacement with a healthy nucleus should suppress tumor growth. However, if cancer originates from dysregulated metabolism originating from mitochondria dysfunction, its substitution with a normal mitochondrion should suppress cancer. Exchange of the nucleus of a cancerous cell (shown in blue) with a normal cell nucleus (shown in red) generates a cybrid that generates cancerous cells despite the absence of tumor-associated genomic abnormalities. The exchange of the nucleus of a normal cell (shown in red) with a cancerous cell nucleus (shown in blue) generates normal cells with distinct morphology despite the presence of tumor-associated genomic abnormalities. Figure created using BioRender.

Figure 2

Mechanisms of glucose metabolic reprogramming in cancer. Hypoxia drives metabolic reprogramming in cancer cells. Increased expression of HIF transcription factors activates oncogenes (i.e., Ras, PI3K-Akt, and c-Myc) or inactivates tumor suppressors (p53 and PTEN) to sustain the glycolytic phenotype of cancer cells. Inactivation of the tumor suppressor gene TP53 is a common feature in cancers and contributes to the enhanced dependence on glycolysis. Inactivation of p53 releases repression of glucose transporters (e.g., GLUT1 and GLUT4) and decreases the expression of TIGAR, a glycolytic inhibitor. Activation of growth factor receptors activate the oncogenic PI3K/Akt pathway and activates downstream targets (FOXOs, HIF1a, c-Myc, and SREBP) that contribute to glucose metabolic reprogramming in cancer cells. Figure created using BioRender.

Figure 3

Glutamine import occurs through glutamine transporters and is utilized in various anabolic pathways such as nucleotides, lipid synthesis, and amino acid synthesis. Cancer cells exhibit a dependence on glutamine (i.e., glutamine addiction), and glutamine catabolism in the mitochondria generates metabolic intermediates to sustain cancer cell biomass. The dependence of cancer cells on glutamine is sustained by alterations in oncogenes and tumor suppressors. Expression of the glutamine transporter SLC1A5 is increased in various cancers to enhance their dependence on glutamine. Activation of the oncogenes KRAS and c-Myc further enhances SLC1A5 expression. The oncogene c-Myc indirectly regulates glutaminolysis through inhibition of miR23a/b, a microRNA involved in regulating GLS1/2 expression. The tumor suppressor p53 upregulates GLS2 expression and enhances glutaminolysis. Glutamine activates the mammalian target of rapamycin complex 1 (mTORC1), which functions to support cancer cell growth. Figure created using BioRender.

Figure 4

Mechanisms of fatty acid metabolic reprogramming. De novo lipogenesis and exogenous uptake of fatty acid both occur to sustain the altered lipid metabolism in cancer cells. The transporters CD36, FATPs, and FABPpm regulate exogenous fatty acid import. Increased CD36 and FATP expression is reported in various cancers. The oncogenic PI3K/Akt pathway is activated to regulate fatty acid metabolism. Activation of SREBPs is key in de novo lipogenesis and catabolism of imported fatty acids. MCT, monocarboxylate transporter; CD36, cluster of differentiation 36; FAs, fatty acids; FATPs, fatty acid transport proteins; FABPpm, fatty acid-binding protein; ACLY, ATP–citrate lyase; ACSS2, acyl-CoA synthetase short-chain family member 2; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SREBPs, sterol regulatory element-binding proteins. Figure created using BioRender.