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

Biomolecules

Olga Mucha¹  Józef Dulak¹  Anna Biela¹  Szczepan Kruczek¹  Kalina Andrysiak¹  Alicja Józkowicz¹  Agnieszka Łoboda¹  Paulina Podkalicka¹  Jacek Stępniewski¹  Kamil Sitarz²  Maciej Mikulski²  Michał Gałęzowski²  Krzysztof Brzózka² 

[1] Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland;Ryvu Therapeutics S.A., Bobrzyńskiego 14, 30-348 Kraków, Poland;

关键词: heme oxygenase-1;    fumarate hydratase;    small-molecule inhibitors;    synthetic lethality hereditary leiomyomatosis and renal cell carcinoma;   

DOI  :  10.3390/biom10010143

来源: DOAJ

【 摘 要 】

Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) 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)—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 HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 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.

【 授权许可】

Unknown