Abstract
Heme oxygenase-1 (HO-1) is induced by a variety of stimuli and plays a multifaceted role in cellular protection. We have shown that HO-1 is overexpressed in thyroid cancer and is associated with tumor aggressiveness. Therefore, we set out to assess the effects of HO-1 inhibitors on the biology of thyroid cancer cells. Two different classes of HO-1 inhibitors were used, including a metalloporphyrin, zinc protoporphyrin-IX (ZnPP), and an azole antifungal agent, ketoconazole. The viability and colony formation of thyroid cancer cells decreased in a concentration- and time-dependent fashion following treatment with HO-1 inhibitors. Cancer cells exhibited a higher sensitivity to HO-1 inhibitors than non-malignant cells. HO-1 inhibitors induced a G0/G1 arrest accompanied by decreased cyclin D1 and CDK4 expressions and an increase in levels of p21 and p27. HO-1 inhibitors significantly increased intracellular ROS levels and suppressed cell migration and invasion. Oxygen consumption rate and mitochondrial mass were increased with ZnPP treatment. Mice treated with ZnPP had a reduced xenograft growth and diminished cyclin D1 and Ki-67 staining in tumor sections. Taken together, HO-1 inhibitors might have therapeutic potential for inducing cell cycle arrest and promoting growth suppression of thyroid cancer cells in vitro and in vivo.
Highlights
The heme oxygenase pathway is an important sensor of cellular stress and regulator of homeostasis [1]
We recently demonstrated that expression of heme oxygenase-1 (HO-1) in thyroid cancer was associated with an advanced tumor stage [6]
We aimed to investigate the effects of these two different classes of pharmacological HO-1 inhibitors on thyroid cancer cells
Summary
The heme oxygenase pathway is an important sensor of cellular stress and regulator of homeostasis [1]. Heme oxygenases are evolutionarily highly conserved enzymes that catalyze the degradation of heme to carbon monoxide, ferrous iron, and the bile pigment biliverdin, which in turn is reduced to bilirubin. There are two different isoforms of heme oxygenases: heme oxygenase-1 (HO-1) and HO-2. The augmented expression of HO-1 in tumor tissues may have detrimental effects as it provides the selective advantage for tumor cells to overcome the increased oxidative stress during tumorigenesis and during treatment [2]. Recent experimental evidence suggests that the inhibition of expression or activity of HO-1 may contribute to an increased efficacy of chemotherapy and improve the outcome in animal models [3]. The therapeutic benefits of HO-1 inhibition have not been tested in clinical trials
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