Antioxidants stimulate BACH1-dependent tumor angiogenesis

Reactive oxygen species (ROS) can inactivate tumor suppressors, activate transcription factors, and stimulate tumor progression, which partly explains the belief that antioxidant supplements should fight cancer. Yet, despite decades of studies, the cancer-fighting potential of antioxidants has never been clearly established. Large clinical trials show that antioxidant supplementation either has no effect or increases cancer risk. Moreover, studies from my host group showed that antioxidants promote malignant melanoma and lung cancer metastasis. Indeed, endogenous and exogenous antioxidants stabilize the transcription factor BTB and CNC homology 1 (BACH1) which increases GAPDH and HK2 gene expression, stimulates aerobic glycolysis, and thus fuels metastasis.

In this thesis I have addressed two questions that arose from the earlier studies. First, as glycolysis is often linked with angiogenesis, I wanted to test the hypothesis that antioxidants through BACH1 can stimulate angiogenesis. Second, our team wanted to study the impact of antioxidant administration on the progression of hematological malignancies, such as B cell lymphoma, where cancer cells can be professional ROS-producing cells, and determine if they respond similarly as solid tumors.

In paper I, we demonstrate that antioxidant-stabilized BACH1 directly controls angiogenesis and glycolysis gene expression in lung cancer spheroids, tumor organoids, and xenograft tumors. Moreover, while HIF1α can control BACH1 expression under both normoxia and hypoxia, BACH1’s ability to stimulate angiogenesis gene expression is HIF1α-independent. In vivo, we found that antioxidant administration increased BACH1-dependent tumor angiogenesis and renders tumors more sensitive to anti-angiogenesis therapy. Notably, BACH1 expression in lung cancer patients’ tumor sections correlates with angiogenesis markers. We conclude that BACH1 is a novel redox and oxygen-sensitive transcription factor.

In paper II, we found that high MYC expression appears to promote proliferation and shield B lymphoma cells from apoptosis at steady-state ROS levels and that compounds such as VitC and NAC in doses that reduce ROS levels induce apoptosis. Injections of VitC and NAC effectively curbed tumor growth from B lymphoma cells with high but not low MYC expression. Consequently, MYC knockdown imparts resistance to VitC and NAC whereas MYC activation makes B cells responsive to these compounds. Mechanistically, VitC and NAC stimulate MYC’s binding to EGR1 via Cys117 of MYC, shifting its transcriptional focus from cell cycle to apoptosis gene expression. Our findings establish a redox-regulated mechanism through which MYC sustains proliferation and averts apoptosis, suggesting a potential use of VitC or NAC as therapeutic agents for MYC-driven B cell lymphoma.

Overall, the studies put forward in this thesis provide a refined understanding of the complex role of ROS, oxidative stress, and antioxidants in cancer.

List of scientific papers

I. Wang T, Dong Y, Huang Z, Zhang G, Zhao Y, Yao H, Hu J, Tüksammel E, Cai H, Liang N, Xu X, Yang X, Schmidt S, Qiao X, Schlisio S, Strömblad S, Qian H, Jiang C, Treuter E, Bergo MO. Antioxidants stimulate BACH1-dependent tumor angiogenesis. J Clin Invest. 2023 Oct 16;133(20):e169671.
https://doi.org/10.1172/JCI169671

II. Yao H, Chen X, Wang T, Kashif M, Qiao X, Tüksammel E, Larsson LG, Okret S, Sayin VI, Qian H, Bergo MO. A MYC-controlled redox switch protects B lymphoma cells from EGR1-dependent apoptosis. Cell Rep. 2023 Aug 29;42(8):112961.
https://doi.org/10.1016/j.celrep.2023.112961