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Arsenic trioxide suppressed mantle cell lymphoma by downregulation of cyclin D1

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Abstract

Mantle cell lymphoma (MCL) is aggressive with poor prognosis. Due to t(11;14)(q13;q32), cyclin D1 is overexpressed. The in vitro activities of arsenic trioxide (As2O3) in MCL were investigated. In MCL lines Jeko-1 and Granta-519, As2O3 induced dose-dependent and time-dependent increases in apoptosis accompanied by cyclin D1 suppression. Downregulation of cyclin D1 resulted in decreased retinoblastoma protein phosphorylation, which led to repressed G1 progression to S/G2 phases. As2O3 did not affect cyclin D1 gene transcription. Instead, As2O3 activated glycogen synthase kinase-3beta (by tyrosine-216 phosphorylation) and IkappaB kinase alpha/beta (by serine-176/180 phosphorylation), both of which phosphorylated cyclin D1 at threonine-286, leading to its poly-ubiquitination and degradation in the proteasome. These observations were recapitulated partly in primary MCL samples obtained from patients refractory to conventional treatment. Our findings suggested that As2O3 might be clinically useful in MCL.

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Acknowledgments

This study was supported in part by the Ruby & Minoo N. Master Charity Fund. The authors thank Alice Cheung for the technical assistance. Dr. Wing-Yan Au obtained the patient samples, and Prof. Gopesh Srivastava provided the cell lines.

Conflict of interest

The University of Hong Kong holds patents from the USA and Japan for the use of oral arsenic trioxide in the treatment of leukemias. The authors are employees of the University of Hong Kong.

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  1. Department of Medicine, Queen Mary Hospital, University of Hong Kong, Professorial Block, Pokfulam Road, Hong Kong, China

    Rico K. H. Lo & Yok-Lam Kwong

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  1. Rico K. H. Lo
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  2. Yok-Lam Kwong
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Correspondence to Yok-Lam Kwong.

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Lo, R.K.H., Kwong, YL. Arsenic trioxide suppressed mantle cell lymphoma by downregulation of cyclin D1. Ann Hematol 93, 255–265 (2014). https://doi.org/10.1007/s00277-013-1866-2

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