Cancer Metabolism | Numiera Therapeutics

Cancer Cell
Metabolism Is Not
All About Sugars.

Since the days of Otto Warburg, most research on cancer cell metabolism has focused on glucose. And for that reason, many people assume that cancer cells primarily use sugars to make energy. But this assumption is out of date, and it is now appreciated that some cancer cells are actually dependent on fatty acids to make energy.

To understand why scientists got so focused on the central role of glucose in cancer cell metabolism, we can take a closer look at how we study cancer in the laboratory, with a focus on malignant brain tumors (also known as glioma).

Many studies of cancer cell metabolism rely on established cell lines, which have been cultured in serum and kept around for many decades. Recent genetic profiling has called into question the integrity of these older cell lines, and it turns out these cells do not maintain the characteristics of the original tumors (Torsvik et al., 2014; Allen et al., 2016). Over the past fifteen years, culturing cells without serum has become standard in the field, because these conditions have been shown to maintain the original features of the human cancer (Lee et al., 2006; Pollard et al., 2009; Fael Al-Mayhani et al., 2009).

Culturing glioma cells in the presence of serum has been shown to alter their epigenetic and biochemical characteristics, leading to deletion of chromosome 18q11-23 (Masters et al., 2001). This genetic region contains multiple protein-encoding genes that play key roles in oxidative metabolism (Huret et al., 2013). These molecular events are thought to underlie the changes that occur after serum exposure, including altered bio-energetic strategies (Lin et al., 2016).

The lesson here is that it is critical to study cancer cells under optimal conditions, to retain their original features (Figure 1).

Why has this fact been neglected for so long?

Figure 1. Glioma cells that support tumor growth express critical enzymes that are required for fatty acid metabolism (Lin et al., 2016).

What metabolic substrates actually fuel growth in glioma cells?

Radiolabeled molecules can help us to track which metabolic substrates actually fuel the growth of cancer cells. These studies have shown that fatty acids and ketones are responsible for more than half of brain tumor metabolism, while glucose contributes much less to overall energy production (Maher et al., 2012; Mashimo et al., 2014). Fatty acids and ketones can be converted into acetyl-CoA, which directly enters the Kreb’s Cycle (Figure 2). By measuring the oxygen consumption rates of cells directly, our team has shown that glioma cells make most of their energy from fatty acids (Lin et al., 2016). And now, many research teams have found that the inhibition of fatty acid metabolism not only reduces cellular respiration, but also glioma cell proliferation and invasion (Lin et al., 2016; Cheng et al., 2020; Kant et al., 2020; Sperry et al., 2020; Jiang et al., 2022).

Figure 2. Fatty acid and ketone metabolism (Strickland & Stoll, 2017).

Are fatty acids the only metabolic substrates needed?

No! Fatty acids and ketones alone are not able to sustain glioma cell proliferation. These cancer cells do require glucose – not to make energy, but to make DNA and RNA (Strickland and Stoll, 2017). Critically, dividing cancer cells must continually produce DNA and RNA to support their malignant growth. To build these key molecules, the glioma cells take up a lot of glucose (Leaver et al., 2002). Glucose is converted into glucose-6-phosphate during the initial steps of glycolysis. That molecule is then diverted through the pentose phosphate pathway (PPP), where it is converted to ribose-5-phosphate. Ribose-5-phosphate is then converted into purine nucleotides with the addition of glutamine, glycine, aspartate, and tetrahydrofolate. Or, ribose-5-phosphate can be converted into pyrimidine nucleotides with the addition of glutamine, aspartate, and bicarbonate. So glucose is necessary to support proliferation – but not because this molecule is needed for energy production, but because it is needed to make DNA and RNA.

How do glioma cells get ahold of fatty acids?

Cancer cells can take fatty acids directly from the bloodstream, or they can make the fatty acids themselves. Interestingly, glucose can actually fuel fatty acid metabolism! In both cell cultures and inside a person, glucose molecules are transported into the cancer cells, converted to fatty acids by the enzyme fatty acid synthase (FASN), then imported into the mitochondria for beta-oxidation. So fatty acids are made and destroyed, in a process known as a futile cycle. Glioma cells in particular express high levels of FASN, and the expression of this enzyme actually increases with tumor malignancy (Tao et al., 2013). Fatty acid synthesis has even been shown to continue under low-oxygen and low-nutrient conditions (Lewis et al., 2015; Jones et al., 2017). The newly-synthesized fatty acids are shuttled into lipid droplets, or little storage centers, during hypoxic conditions – so they can support cancer cell growth and survival upon re-oxygenation (Bensaad et al., 2014).

How do glioma cells use fatty acids to make energy?

Once fatty acids are made within the cell, or taken up from the bloodstream, they are converted into molecules called acyl-carnitines. The acyl-carnitines are then transported into the mitochondria by a carnitine transporter called carnitine transporter 1 (CPT1). Once inside the mitochondria, the fatty acids are dehydrogenated and thiolized, with each iteration breaking off two carbons - an acetyl coA molecule! The end result of this process is the release of many molecules of energy-rich acetyl-CoA, which can fuel oxidative respiration through the electron transport chain (Figure 3).

Figure 3. A schematic showing how acetyl-CoA connects fatty acid metabolism to the electron transport chain (Strickland & Stoll, 2017).

So why are glioma cells also undergoing glycolysis?

As we learned above, glycolysis supports not only energy production, but the production of DNA and RNA for growing cancer cells! And the breakdown of glucose molecules occurs alongside the oxidation of fatty acids (Randle et al., 1963). In fact, NADH and ATP produced in the course of fatty acid oxidation promote the conversion of glucose into lactate and other molecules - leading to an acidification of the tumor microenvironment, which permits cancer cell invasion, and the production of even more nucleic acids, which helps the cancer cells to replicate their DNA (Holness and Sugden, 2003). For this reason, the oxidation of fatty acids in the mitochondria is highly compatible with ongoing glycolysis, and in fact can actually promote the Warburg Effect in cancer cells. The reverse is also true: A recent study established the Corbet-Feron Effect, where lactate-induced acidification of the tumor microenvironment over time leads to adaptation of some cancer cells, actually promoting fatty acid oxidation as a metabolic strategy (Corbet et al., 2016).

Fatty acids are critical for glioma growth and malignancy.

Fatty acids are the primary source of energy in some cancer types. Blocking this important metabolic pathway leads to an 80% decrease in the amount of energy produced by glioma cells, and a significant reduction in the growth of glioma cells (Lin et al., 2016). And importantly, fatty acids not only provide substrates for energy production; they can also be used to make useful raw materials which further support cancer cell growth (Strickland & Stoll, 2017). That is why we are blocking this important pathway - to stop the growth of malignant brain tumors and other cancers.

Cancer Cell Metabolism Is Not All About Sugars.