Regulation of PSMB5 and {beta}-Subunits of Mammalian Proteasome by Constitutively Activated STAT3: Potential Role in Bortezomib Mediated Anticancer Therapy [Cell Biology]

March 13th, 2014 by Vangala, J. R., Dudem, S., Jain, N., Kalivendi, S. V.

Ubiquitin-proteasome system facilitates the degradation of ubiquitin-tagged proteins and performs a regulatory role in cells. Elevated proteasome activity and subunit expression are found in several cancers. However, the inherent molecular mechanisms responsible for increased proteasome function in cancers remain unclear, despite well investigated and defined role of the mammalian proteasome. The present study was initiated to elucidate the mechanisms involved in the regulation of β-subunits of the mammalian proteasome. Suppression of STAT3 tyrosine phosphorylation coordinately decreased the mRNA and protein levels of the β-subunits of 20S core complex in DU145 cells. Notably PSMB5, a molecular target of bortezomib, was shown to be a target of STAT3. Knockdown of STAT3 decreased PSMB5 protein. Inhibition of phospho-STAT3 substantially reduced PSMB5 protein levels in cells expressing constitutively active-STAT3. Accumulation of activated STAT3 resulted in the induction of PSMB5 promoter and protein levels. In addition, a direct correlation was observed between the endogenous levels of PSMB5 and constitutively active STAT3. PSMB5 and STAT3 protein levels remain unaltered following inhibition of proteasome activity. EGF-induced concerted increase of β-subunits was blocked by inhibition of EGFR or STAT3 but not by PI3K/AKT or MEK/ERK pathways. Decreased proteasome activities were due to reduced protein levels of catalytic subunits of proteasome in STAT3-inhibited cells. Combined treatments with bortezomib and inhibitor of STAT3 abrogated proteasome activity and enhanced cellular apoptosis. Overall, we demonstrate that aberrant activation of STAT3 regulates the expression of β-subunits, in particular PSMB5, and regulates the catalytic activity of proteasome.
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