High Hemin Concentration Induces Escape from Senescence of Normoxic and Hypoxic Colon Cancer Cells

SIMPLE SUMMARY: High red-meat consumption as well as bleeding or bruising can promote oxidative stress and, in consequence, cancer development. However, the mechanism of that phenomenon is not understood. The induction of therapy-induced senescence (TIS) might also be induced by oxidative stress. Recently, TIS cells, despite their inhibited proliferation potential, have been identified as one of the sources of tumor re-growth. Here, with the use of molecular analyses, we found that oxidative stress, promoted by high doses of hemin or H(2)O(2), can trigger TIS escape and cell re-population. It is closely related to the activity of antioxidative enzymes, especially heme oxygenase-1. Hypoxia might accelerate these effects. Therefore, we propose that the prevention of excessive oxidative stress could be a potential target in senolytic therapies. ABSTRACT: Hemoglobin from either red meat or bowel bleeding may promote oxidative stress and increase the risk of colorectal cancer (CRC). Additionally, solid cancers or their metastases may be present with localized bruising. Escape from therapy-induced senescence (TIS) might be one of the mechanisms of tumor re-growth. Therefore, we sought to study whether hemin can cause escape from TIS in CRC. To induce senescence, human colon cancer cells were exposed to a chemotherapeutic agent irinotecan (IRINO). Cells treated with IRINO exhibited common hallmarks of TIS. To mimic bleeding, colon cancer cells were additionally treated with hemin. High hemin concentration activated heme oxygenase-1 (HO-1), induced escape from TIS and epithelial-to-mesenchymal transition, and augmented progeny production. The effect was even stronger in hypoxic conditions. Similar results were obtained when TIS cells were treated with another prooxidant agent, H(2)O(2). Silencing of antioxidative enzymes such as catalase (CAT) or glutathione peroxidase-1 (GPx-1) maintained colon cancer cells in a senescent state. Our study demonstrates that a high hemin concentration combined with an increased activity of antioxidative enzymes, especially HO-1, leads to escape from the senescence of colon cancer cells. Therefore, our observations could be used in targeted anti-cancer therapy.