Antioxidants enhance lung cancer metastasis by stabilizing BACH1

By Will Boggs MD

NEW YORK (Reuters Health) - 8/7/2019

Antioxidants can contribute to lung cancer metastasis by stabilizing the transcription factor BACH1, researchers report.

"We believe it is time that physicians and regulatory bodies warn people about this potential danger," Dr. Martin O. Bergo from Karolinska Institutet, Huddinge and University of Gothenburg, Sweden told Reuters Health by email. "Cancer patients are, according to some studies, more likely than healthy people to resort to alternative medicines and to rely on dietary changes and supplements to help them with their cancer. The marketing of these products to cancer patients should be stopped. The Swedish radiation safety authority is the first agency, to my knowledge, to go public with such a warning (for malignant melanoma patients)."

Cancer cells produce high levels of reactive oxygen species (ROS), and the belief that ROS stimulates tumor initiation and progression has prompted many people to supplement their diets with antioxidants, despite many randomized clinical trials that have disproven this strategy. In fact, emerging evidence suggests that ROS creates barriers to tumor progression that antioxidant supplements can help cancer cells overcome.

Dr. Bergo and colleagues combined long-term studies in mouse models with genomic, metabolic, and data mining approaches to investigate the impact of ROS and antioxidants in lung cancer metastasis.

In mouse models, the antioxidants N-acetylcysteine (NAC) and vitamin E stimulated lung cancer metastasis independent of p53, and chronic antioxidant administration reduced ROS and increased lung cancer cell invasiveness.

Antioxidants stabilized the transcription factor BACH1, which was required for antioxidants to induce metastasis, although BACH1 was also able to induce metastasis to a lesser degree in the absence of antioxidants, according to the June 27th Cell online report.

BACH1 stimulated metastasis by up regulating glycolytic enzymes, especially hexokinase 2 (Hk2) and Gapdh, and antioxidants stimulated glycolysis only in the presence of BACH1.

Drugs targeting enzymes associated with glycolysis prevented antioxidant- and BACH1-stimulated metastasis.

"The mechanism exposes a previously unknown weakness in lung cancer cells that can be targeted therapeutically," Dr. Bergo said. "Targeting BACH1, the BACH1-target gene heme oxygenase 1 (HO-1), or one of several glycolysis-related enzymes (HK2, GAPDH, and the lactate transporter) were all effective strategies in cells and mouse models to prevent antioxidant-induced metastasis. For some of those strategies, drugs already exist that can be tested further in preclinical conditions and potentially phase I clinical trials."

In a related report, also published in Cell, Dr. Thales Papagiannakopoulos from New York University School of Medicine, New York City, and colleagues describe the molecular mechanisms by which accumulation of Nrf2, the master transcriptional regulator of the cell's antioxidant program, promotes metastasis in lung cancer.

Nrf2 accumulation in lung cancers stabilized BACH1 by inhibiting its degradation (partly by inducing Ho-1, the enzyme that catabolizes heme), thereby promoting lung cancer metastasis.

"Targeting the heme pathway to increase heme levels either by regulating heme synthesis or its degradation by Ho-1 might prove a potential therapeutic approach to suppress the metastatic spread of KEAP1/NRF2 mutant tumors (~30% of non-small-cell lung cancer (NSCLC) patients)," Dr. Papagiannakopoulos said in an email. "This is important because several recent clinical studies have shown that KEAP1/NRF2 mutant tumors are very aggressive and have the worst clinical prognosis of all other patients with NSCLC. It may be possible to repurpose compounds used for the treatment of porphyrias for the use in patients with KEAP1/NRF2 mutations."

"Most clinical tests currently assess the mutation status of EGFR, KRAS, EML4-ALK and ROS1 fusions, but do not assess the mutation status of other frequent mutation such as KEAP1/NRF2," he said. "These mutations drive very important biological mechanism that promote tumor growth and metastasis that should be therapeutically targeted."

"Together, (these complementary studies) demonstrate that stabilized BACH1 is central to metastasis in NSCLC, and identifies two novel targets for therapeutic intervention that either destabilize BACH1 or disrupt a BACH1 transcriptional program," write Dr. Nicole M. Anderson and Dr. M. Celeste Simon from Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania in a related editorial.

"Both studies strongly suggest that KEAP1/NRF2 mutations could represent an excellent biomarker for these interventions," they note.

SOURCE: http://bit.ly/2xzhcnc, http://bit.ly/2xBAqbP and http://bit.ly/2xxHHJQ

Cell 2019.

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