Heme oxygenase-1 inhibitors induce cell cycle arrest and suppress tumor growth in thyroid cancer cells

Po Sheng Yang, Yi Chiung Hsu, Jie Jen Lee, Ming Jen Chen, Shih Yuan Huang, Shih Ping Cheng

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Article number2502
JournalInternational Journal of Molecular Sciences
Volume19
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • Heme oxygenase
  • Metabolism
  • Reactive oxygen species
  • Thyroid cancer

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