Abstract 3619: Arsenic trioxide downregulates NPM-ALK and inhibits the proliferation of ALK-positive anaplastic large cell lymphoma

Autor: David Hw Chau, Wenying Piao, Yok-Lam Kwong, Eric W. C. Tse, Kevin Lm Yue
Rok vydání: 2015
Předmět:
Zdroj: Cancer Research. 75:3619-3619
ISSN: 1538-7445
0008-5472
Popis: INTRODUCTION Anaplastic Large Cell Lymphoma (ALCL) is a mature T-cell lymphoma. Depending on the presence or absence of chromosomal translocations involving the anaplastic lymphoma kinase ALK gene and hence the expression of ALK, ALCL is further subdivided into ALK positive (ALK+) or ALK negative (ALK-) types. NPM-ALK chimeric fusion oncogenic protein is found in around 80% of ALK+ ALCL, as a result of the chromosomal translocation t(2;5)(p23;q35). The current standard of treatment for ALK+ ALCL is combination chemotherapy. Crizotinib, an ALK tyrosine kinase inhibitor, is the only agent available to target NPM-ALK in ALCL. The identification of other targeting agents would potentially improve the treatment outcome of ALK+ ALCL especially for relapsed and/or refractory cases. In this study, we investigated the effect of arsenic trioxide (As2O3) on NPM-ALK in ALCL. Methods We treated ALK+ ALCL cell lines with various clinically achievable concentrations of As2O3 (0, 0.5, 1 and 2μM) for 24 hours and examined its effects on NPM-ALK mRNA expression by semi-quantitative RT-PCR and protein expression by Western immunoblotting. The downstream signaling pathway of NPM-ALK, phosphorylation of STAT3 on Tyr705, was also examined. Next, we analyzed apoptotic cell death and growth arrest induced by As2O3 in ALK+ and ALK- ALCL cell lines using Annexin V-7AAD staining and cell cycle analysis. The effect of As2O3 on cell viability was also measured with WST-1 assay. RESULTS Our data showed that As2O3 downregulated NPM-ALK at the protein level without affecting the transcription. It also inhibited the phosphorylation of STAT3 in all ALK+ ALCL cell lines. We also found that blocking protein degradation through proteasome with MG132 abrogated the effect of As2O3 on NPM-ALK. Furthermore, As2O3 induced apoptotic cell death, cell cycle arrest at G2/M phase and growth inhibition in ALK+ but not in ALK- ALCL cell lines, with a GI50 of less than 1μM, which was a level achievable with clinical use of As2O3. CONCLUSIONS. Our data demonstrated that As2O3 downregulated NPM-ALK by facilitating protein degradation through the proteasomal pathway, thereby inhibited cell proliferation and induced cell death in ALK+ ALCL. As2O3 may therefore represent a potential therapeutic agent for the treatment of ALK+ ALCL. Citation Format: Wenying Piao, David HW Chau, Kevin LM Yue, Yok Lam Kwong, Eric WC Tse. Arsenic trioxide downregulates NPM-ALK and inhibits the proliferation of ALK-positive anaplastic large cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3619. doi:10.1158/1538-7445.AM2015-3619
Databáze: OpenAIRE
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