Anticancer activity of Neosetophomone B by targeting AKT/SKP2/MTH1 axis in leukemic cells

Shilpa Kuttikrishnan; Ajaz A Bhat; Jericha M Mateo; Fareed Ahmad; Feras Q Alali; Tamam El-Elimat; Nicholas H Oberlies; Cedric J Pearce; Shahab Uddin

doi:10.1016/j.bbrc.2022.02.071

Anticancer activity of Neosetophomone B by targeting AKT/SKP2/MTH1 axis in leukemic cells

Biochem Biophys Res Commun. 2022 Apr 23:601:59-64. doi: 10.1016/j.bbrc.2022.02.071. Epub 2022 Feb 22.

Authors

Shilpa Kuttikrishnan¹, Ajaz A Bhat², Jericha M Mateo³, Fareed Ahmad⁴, Feras Q Alali⁵, Tamam El-Elimat⁶, Nicholas H Oberlies⁷, Cedric J Pearce⁸, Shahab Uddin⁹

Affiliations

¹ Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
² Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, Qatar.
³ Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
⁴ Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
⁵ College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Qatar.
⁶ Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
⁷ Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, 27402, United States.
⁸ Mycosynthetix, Inc., Hillsborough, NC, 27278, United States.
⁹ Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory of Animal Research Center, Qatar University, Doha, Qatar. Electronic address: SKhan34@hamad.qa.

PMID: 35228122
DOI: 10.1016/j.bbrc.2022.02.071

Abstract

Neosetophomone B (NSP-B), a meroterpenoid fungal secondary metabolite, was investigated for its anticancer potential in leukemic cell lines (K562 and U937). NSP-B treatment of leukemic cells suppressed cell viability by triggering apoptotic cell death. Apoptosis induced by NSP-B is triggered by mitochondrial signaling and caspase activation. Additionally, NSP-B treatment of leukemic cells causes AKT's inactivation accompanied by downregulation of SKP2 oncogene and MTH1 with a concomitant increase of p21Cip1and p27Kip1. Furthermore, NSP-B causes suppression of antiapoptotic proteins, including cIAP1, cIAP2, XIAP, survivin and BCl-XL. Overall, NSP-B reduces cell viability by mitochondrial and caspase-dependent apoptosis. The inhibition of AKT and SKP2 axis could be a promising therapeutic target for leukemia treatment.

Keywords: Apoptosis; Fungal secondary metabolites; Leukemia; Meroterpenoids; Natural products; Neosetophomone B.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Cell Survival / drug effects
DNA Repair Enzymes* / metabolism
Humans
K562 Cells
Leukemia*
Phosphoric Monoester Hydrolases* / metabolism
Proto-Oncogene Proteins c-akt* / metabolism
S-Phase Kinase-Associated Proteins* / metabolism
Signal Transduction / drug effects
Terpenes* / pharmacology
U937 Cells

Substances

S-Phase Kinase-Associated Proteins
SKP2 protein, human
Terpenes
Proto-Oncogene Proteins c-akt
Phosphoric Monoester Hydrolases
8-oxodGTPase
DNA Repair Enzymes