Antioxidants are chemical compounds that scavenge the free, chemically unstable molecules called reactive oxygen species (ROS) radicals, which can react with DNA and leads to the progression of various diseases including cancer. DNA is a major target of free radical damage. These damages can culminate into mutations that are heritable change in the DNA, which can lead to cancer. Our body generates endogenous antioxidants in order to quench these free radicals. However, our body system preferably counts upon the external sources of antioxidants, referred to as the “exogenous antioxidants”. These exogenous sources include dietary antioxidants like- Vitamin A, C, and E, beta-carotene, etc [1]. These antioxidants are believed to dispense a panacea of benefits.
Lung cancer commencing in the lungs begins to metastasize, it spreads through the lymph nodes to the brain and other parts of the body making it the deadliest of all cancer. The metastatic cascade involves a multitude of steps which include- Epithelial-Mesenchymal Transition (EMT), intravasation, evading the immune system, survival in circulation, extravasation, and colonization in a distant organ [2]. Cancer cells generate high levels of reactive oxygen species (ROS) by altering the signaling and metabolic pathways. For decades, the notion that ROS stimulates tumor initiation and progression has prompted healthy people and cancer patients to supplement their diet with antioxidants.
In recent decades, scientists have been shoving up antioxidants in cell cultures, humans, mice rats, etc. to confer the beneficial role of antioxidants. A series of studies have sparked up with the controversial roles of antioxidants. Antioxidants once touted as a cancer preventive, are now anticipated in spurring up the progression of the disease which was evident from some randomized clinical trials. A 1994 cancer prevention study entitled “The Alpha-Tocopherol (vitamin E)/ Beta-Carotene Cancer Prevention Study (ATBC)” exemplified that daily intake of beta-carotene enhanced lung cancer rates significantly in Finnish male smokers; however, they were not affected by vitamin E [3].
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The blanket knowledge regarding antioxidants that they can help fight cancer has been gainsaid when researchers recently discovered that antioxidants hasten the progression of cancerous cells. In 2014, two independent research teams, one led by Dr. Martin Bergo at the Karolinska Institute and Gothenburg University in Sweden and, the other at New York University, US showed that antioxidant supplements, such as vitamin E, fueled up the tumor growth. Since then, follow-up researches providing compelling evidence that antioxidants have pro-tumorigenic activity have been conducted.
In 2019, the same group conducted a study to further explain how antioxidants boost cell growth and promote lung cancer metastasis. The study involves the role of heme, or ‘‘iron protoporphrin IX,’’. Various forms of oxidative stress elicit heme release from heme-containing proteins which exacerbates oxidative stress as free heme catalyzes a massive creation of free radicals. Heme oxygenase-1 (HO-1) plays a pivotal role in regulating the intracellular levels of free heme. Dr. Bergo’s team unveiled a new idea that supplementation of antioxidants stabilizes a transcription factor called BACH1 (BTB and CNC homology 1) [4].
BACH1 belongs to the cap’n’collar (CNC) b-Zip family of proteins is a key factor in responding to conditions of oxidative stress, as it directly binds to AREs in promoters of antioxidant genes, and acts as a molecular sensor of intracellular heme levels [5]. Under physiological conditions, NRF2 is degraded by KEAP1, a substrate receptor of a CRL3 (CUL3 RING ubiquitin ligase) complex [6]. In response to oxidative stress, Nrf2 accumulates through Keap1 inactivation, and increased levels of free heme stimulate HO-1 expression by directly binding to the antioxidant response elements (AREs) within the HO-1 promoter [7].
The free heme promotes the proteasome-dependent degradation of Bach1. However, excess supplementation of antioxidants reduces the oxidative stress which causes low levels of heme and thus stabilization of BACH1. BACH1 is considered to displace NRF2 from ARE and causes the transcriptional repression of HO-1. Stabilized BACH1 and its accumulation contribute to metastasis by activating the transcription of Hexokinase 2 and Gapdh which results in enhanced glycolysis rate, glucose uptake and lactate secretion [4, 8].
The scientists have demonstrated that antioxidant-induced BACH1 stabilization increases the proficiency of the metastasis. In order to demolish the progression of the cancerous cell, two novel targets for therapeutic intervention have been identified which includes either destabilization of BACH1 or by inhibiting heme oxygenase, which is linked to BACH1, can also restraint the metastasis process.
References:
- Machlin, L. J., & Bendich, A. (1987). Free radical tissue damage: protective role of antioxidant nutrients. The FASEB journal, 1(6), 441-445.
- Geiger, T. R., & Peeper, D. S. (2009). Metastasis mechanisms. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1796(2), 293-308.
- Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. (1994). The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine, 330(15), 1029-1035.
- Wiel, C., Le Gal, K., Ibrahim, M. X., Jahangir, C. A., Kashif, M., Yao, H., … & Kanduri, C. (2019). BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell, 178(2), 330-345.
- Ogawa, K., Sun, J., Taketani, S., Nakajima, O., Nishitani, C., Sassa, S., … & Igarashi, K. (2001). Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. The EMBO journal, 20(11), 2835-2843.
- Menegon, S., Columbano, A., & Giordano, S. (2016). The dual roles of NRF2 in cancer. Trends in molecular medicine, 22(7), 578-593.
- Chiang, S. K., Chen, S. E., & Chang, L. C. (2019). A dual role of Heme Oxygenase-1 in cancer cells. International journal of molecular sciences, 20(1), 39.
- Lignitto, L., LeBoeuf, S. E., Homer, H., Jiang, S., Askenazi, M., Karakousi, T. R., … & Sayin, V. I. (2019). Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1. Cell, 178(2), 316-329.
