Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

• Main Authors: Paulina Podkalicka, Olga Mucha, Szczepan Kruczek, Anna Biela, Kalina Andrysiak, Jacek Stępniewski, Maciej Mikulski, Michał Gałęzowski, Kamil Sitarz, Krzysztof Brzózka, Alicja Józkowicz, Józef Dulak, Agnieszka Łoboda
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Biomolecules
• Subjects: heme oxygenase-1; fumarate hydratase; small-molecule inhibitors; synthetic lethality hereditary leiomyomatosis and renal cell carcinoma
• Online Access: https://www.mdpi.com/2218-273X/10/1/143

Elevated expression of heme oxygenase-1 (HO-1, encoded by <i>HMOX1</i>) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)&#8212;an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including <i>HMOX1</i> and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of <i>HMOX1</i> resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed.