Antioxidants implicated in lung cancer metastasis

By Liz Meszaros, MDLinx
Published July 17, 2019

Key Takeaways

Antioxidants may actually promote cancer metastasis in individuals with lung cancer, according to results from two separate studies.

Researchers have discovered that antioxidants are used by lung cancer cells to activate Bach1, a protein that actually increases the uptake and synthesis of sugar by cancer cells, thereby promoting metastasis. They published their results in Cell.

Antioxidants, such as vitamins A, C, and E, all act to counter oxidative stress in the body. Oxidative stress—which occurs when there’s an imbalance between the body’s production of free radicals and its ability to neutralize free radicals and free-radical-induced damage with antioxidants—releases free-floating heme, an oxygen-carrying pigment that causes further molecular damage. As a protective measure, healthy cells release heme oxygenase-1 (Ho-1), an enzyme that clears the excess heme. In lung cancer cells, however, this protective measure is commandeered and excess heme cannot be cleared.

But, here’s the rub. Heme has an important function: It degrades the Bach1 protein. Without heme, Bach1 builds up in cancer cells and activates the genes that drive cancer metastasis.

In addition, about 30% of lung cancers have NRF2 and KEAP1 mutations, which enables them to produce their own antioxidants that are then used to reduce oxidative stress. When antioxidants are supplied by the diet or through supplements—think vitamins A, C, or E—they are also used by lung cancer cells to decrease their oxidative stress. This, in turn, stabilizes Bach1 and allows it to accumulate in the cells.

Bach1 then stimulates the mechanisms that lead to metastasis within the cells themselves, such as increased glucose metabolism—which converts sugars into cellular fuel and lactic acid—and the hijacking of glucose from the blood stream. This high glucose metabolism than promotes the cancer cells’ ability to spread.

Complementary study findings

In the first study, senior author Martin Bergö, PhD, molecular biologist, Karolinska Institutet, Stockholm, Sweden, and colleagues treated mutant mice and human lung cancer cells with antioxidants to duplicate the effects of taking dietary supplements. This team of researchers had previously demonstrated that doses of antioxidant supplements, such as vitamin E, accelerated primary tumor growth in mice. This was a controversial finding, as antioxidants have been thought to have beneficial effects against cancer.  

In the current study, Dr. Bergö and colleagues found that antioxidants elevated Bach1 levels, and that the Bach1 “turned on” the genes (NRF2 and KEAP1) that accelerate glucose uptake and use. This, in turn, initiated aggressive metastasis.

Thus, stopping the production of Bach1 and/or blocking glycolysis would both, theoretically, stop or slow cancer metastasis.

In the second study, Michele Pagano, MD, chairman, Department of Biochemistry and Molecular Pharmacology, New York University of Medicine, New York, NY, and colleagues found that advanced-stage and metastasized tumors in human tissues had high levels of both Bach1 and Ho1.

Both studies shed light on the mechanisms behind the promotion of cancer through antioxidants and both teams of researchers are hopeful that their results may help find new therapeutic agents that can inhibit Ho1, block the production of Bach1, or prevent glycolysis in lung and other cancers.

“The results provide a new mechanism for how lung cancer cells can spread and may lead to new possibilities for treatment. We now have important new information on lung cancer metastasis, making it possible for us to develop new treatments, such as ones based on inhibiting Bach1,” concluded Dr. Bergö.

Dr. Bergö’s study was supported grants from the Knut and Alice Wallenberg Foundation, the Sjöberg Foundation, StratCan (the strategic research program in cancer at Karolinska Institutet), CIMED (the Centre for Innovative Medicine at Karolinska Institutet), the Swedish Cancer Society, the Swedish Research Council, the Swedish Society for Medical Research, the Wallenberg Center for Molecular and Translational Medicine, and the Alex and Eva Wallström Foundation.

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