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Cytotoxic effects of Bortezomib in Myelodysplastic syndrome/Acute Myeloid Leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

ABSTRACT: Bortezomib (Velcade©) is widely used for the treatment of various human cancers, however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that Bortezomib induces proteasome-independent degradation of TRAF6 protein, but not mRNA, in Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with Bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized Bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in Bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of Bortezomib due to down-regulation of the proteasomal subunit alpha-1 (PSMA1). To uncover the molecular consequences following loss of TRAF6 in MDS/AML cells, we applied gene expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe novel mechanisms by which TRAF6 is regulated through Bortezomib/autophagy-mediated degradation and by which it alters MDS/AML sensitivity to Bortezomib by controlling PSMA1 expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38519 | GEO | 2012/06/15

SECONDARY ACCESSION(S): PRJNA168095

REPOSITORIES: GEO

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Cytotoxic effects of Bortezomib in Myelodysplastic syndrome/Acute Myeloid Leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

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