Researchers reveal vulnerabilities of 'addicted' cancer cells

By Samantha Black, PhD, The Science Advisory Board editor in chief

March 30, 2020 -- New findings about the mechanism by which some cancer cells can become "addicted" to glucose could lead to fresh approaches to targeted cancer therapies. The results of the research were published in Nature Cell Biology on March 30.

Metabolic reprogramming often makes cancer cells highly dependent on specific nutrients for survival. Therefore, in the current paper, researchers suggest that limiting the supply of those nutrients or blocking their uptake or metabolism would selectively kill the "addicted" cancer cells.

As an example, asparaginase can be used to treat acute lymphoblastic leukemia because these enzymes lack asparagine synthetase and are therefore highly dependent on exogenous asparagine for survival. The treatment disrupts asparagine supply, ensuring that cancer cells cannot receive the vital amino acid and resulting in cancer cell death.

In the current study, the researchers focused on the amino acid cysteine. It contributes to cellular redox homeostasis, ensuring the removal of toxic compounds, and is a rate-limiting precursor for glutathione biosynthesis. Cancer cells rely on cysteine to maintain strong antioxidant defenses. Most obtain cysteine through uptake of extracellular cystine -- the oxidized dimer of cysteine -- via solute carrier family 7 member 11 (SLC7A11). Once inside the cancer cell, cystine is reduced to cysteine to fuel glutathione biosynthesis.

"SLC7A11 is frequently overexpressed in cancers and has a well-established role in maintaining glutathione levels which reduce cancer cell death," said Boyi Gan, PhD, of the Department of Experimental Radiation Oncology at MD Anderson Cancer Center, in a statement.

Boyi Gan, PhD
Boyi Gan, PhD. Image courtesy of the University of Texas MD Anderson Cancer Center.

Cells need to maintain appropriate levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH) to maintain redox homeostasis. Typically, the pentose phosphate pathway (PPP) is the major NADPH supplier and biosynthesis processes are the major NADPH consumer.

However, in cancer cells with high SLC7A11 expression and cystine uptake, cystine reduction to cysteine can also be an important NADPH consumer. This process comes at a significant cost to cancer cells. Accumulation of intracellular cystine, the least soluble amino acid, can be toxic to cells.

Therefore, cancer cells with high SLC7A11 expression must rapidly reduce cystine to cysteine in order to maintain nontoxic levels, which requires NADPH and consequently PPP. As long as sufficient glucose is provided to PPP, then redox homeostasis in SLC7A11-overexpressing cancer cells can be maintained.

Understanding this mechanism reveals a metabolic vulnerability associated with high SLC7A11 expression in cancer cells and points researchers toward potential therapeutic strategies. Gan et al suggest that limiting NADPH production from the PPP by glucose starvation with the use of glucose transporter (GLUT) inhibitors can lead to a massive accumulation of small-molecule disulfides (including cystine). This selectively kills SLC7A11-high cancer cells and suppresses SLC7A11 tumor growth.

The researchers found GLUT inhibition by KL-11743, a recently developed GLUT1 and GLUT3 inhibitor, had a tumor-suppressive effect across a broad range of lung cancer cell lines or preclinical models. Specifically, KL-11743 showed no growth effect on SLC7A11-low cells but significantly suppressed the growth of all SCL7A11-high cells.

As high expression of SLC7A11 in cancer cells is associated with specific mutations such as the loss of BAP1 or KEAP1 tumor suppression, the researchers suggest that they may serve as potential biomarkers in selecting cancer patients with high SLC7A11 expression for GLUT inhibition.

"Limiting the supply of such nutrients or blocking their uptake or metabolism through pharmacological means may selectively kill 'addicted' cancer cells without affecting normal cells," said Gan. "Our understanding of nutrient dependency in cancer cells can provide great insights for targeting metabolic vulnerabilities in cancer therapies."


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