The aggresome pathway as a target for therapy in hematologic malignancies

Abstract

Misfolded or unfolded proteins are often refolded with the help of chaperones or degraded by the 26S proteasome. An alternative fate of these proteins is the aggresome pathway. The microtubule-organizing center (MTOC) transports unfolded proteins to lysosomes and are degraded through autophagy. Histone deacetylase 6 (HDAC6) deacetylates alpha-tubulin, which is thought to be a component of the MTOC. Recently, two small molecule inhibitors of the aggresome pathway and HDAC6 have been described. One inhibitor, tubacin, prevents deacetylation of alpha-tubulin and produces accumulation of polyubiquitinated proteins and apoptosis. Tubacin acts synergistically with the proteasome inhibitor, bortezomib, to induce cytotoxicity in one type of hematologic malignancy, multiple myeloma. The other, LBH589, is a pan HDAC inhibitor and hydroxamic acid derivative that induces apoptosis of multiple myeloma cells resistant to conventional therapies. In this review, we summarize recent reports on targeting the aggresome pathway and HDAC6 in hematologic malignancies.

Figure 1

The aggresome pathway prevents accumulation of misfolded proteins. Unfolded or misfolded protein can originate from translating polysomes, from proteins retrotranslocated from the ER to the cytosol, or from proteins damaged by stress. If such proteins fail to fold correctly and are not degraded by the proteasome, they can form aggregates in cells. These aggregates are transported by the microtubule and require the dynein/dynactin motor complex. HDAC6 (dotted arrow) deacetylates α-tubulin and associates with dynein (dotted arrow) to facilitate transport of aggresomes through the cytosol for degradation. Tubacin and LBH589 are small molecule inhibitors that target HDAC6 or pan HDACs, respectively, resulting in increased acetylation of α-tubulin, accumulation of polyubiquitinated proteins, and apoptosis [25, 31].