Journal
MOLECULAR GENETICS AND METABOLISM
Volume 94, Issue 3, Pages 283-286Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2008.03.012
Keywords
aggresomes; protein degradation; multiple myeloma; apoptosis; HDAC6; alpha-tubulin
Funding
- NCI NIH HHS [T32 CA009056, T32CA9056] Funding Source: Medline
- NHLBI NIH HHS [HL83077, T32 HL086345, HL75826, T32HL086345, R01 HL075826, T32 HL086345-02, R01 HL083077] Funding Source: Medline
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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 cc-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. (c) 2008 Elsevier Inc. All rights reserved.
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