Lasonolide A, a potent and reversible inducer of chromosome condensation

Abstract

Lasonolide A (LSA) is a natural product with high and selective cytotoxicity against mesenchymal cancer cells, including leukemia, melanomas and glioblastomas. Here, we reveal that LSA induces rapid and reversible premature chromosome condensation (PCC) associated with cell detachment, plasma membrane smoothening and actin reorganization. PCC is induced at all phases of the cell cycle in proliferative cells as well as in circulating human lymphocytes in G₀. It is independent of Cdk1 signaling, associated with cyclin B downregulation and induced in cells at LSA concentrations that are three orders of magnitude lower than those required to block phosphatases 1 and 2A in vitro. At the epigenetic level, LSA-induced PCC is coupled with histone H3 and H1 hyperphosphorylation and deacetylation. Treatment with SAHA reduced LSA-induced PCC, implicating histone deacetylation as one of the PCC effector mechanisms. In addition, PCC is coupled with topoisomerase II (Top2) and Aurora A hyperphosphorylation and activation. Inhibition of Top2 or Aurora A partially blocked LSA-induced PCC. Our findings demonstrate the profound epigenetic alterations induced by LSA and the potential of LSA as a new cytogenetic tool. Based on the unique cellular effects of LSA, further studies are warranted to uncover the cellular target of lasonolide A (“TOL”).

Keywords: :

• Histone H3 phosphorylation
• histone H3 deacetylation
• chromosome condensation
• Maturation Promoting Factor
• topoisomerase II
• Aurora kinase

Disclosure of Potential Conflicts of Interest

No potential conflicts of interests were disclosed.

Acknowledgments

Our studies are supported by the Center for Cancer Research, National Cancer Institute Intramural Program. We wish to thank Ernest Hamel, Toxicology and Pharmacology Branch, Developmental Therapeutics Program, National Cancer Institute, Frederick, MD for bringing LSA to our attention and providing initial drug samples. We also wish to thank Kiyung S. Lee, Laboratory of Metabolism, CCR-NCI, Bethesda for discussions and for suggesting or providing the Aurora and Plk inhibitors.