TY - JOUR
T1 - The aggresome pathway as a target for therapy in hematologic malignancies
AU - Simms-Waldrip, Tiffany
AU - Rodriguez-Gonzalez, Agustin
AU - Lin, Tara
AU - Ikeda, Alan K.
AU - Fu, Cecilia
AU - Sakamoto, Kathleen M.
N1 - Funding Information:
T.S.W. is funded by a grant from the American Academy of Pediatrics. A.R.G. is supported by the Department of Defense (W81XWH-06-1-0192) and the MEC/Fulbright fellowship (EX2005-0517). T.L. is funded by the NIH postdoctoral fellowship (T32HL086345). A.K.I. is supported by the NIH postdoctoral fellowship (T32CA9056). K.M.S. is supported by the National Institutes of Health Grants HL75826 and HL83077, American Cancer Society Grant RSG-99-081-01-LIB, Department of Defense (CM050077), and the Leukemia and Lymphoma Society Translational Research Grant (6019-07). K.M.S. is a Scholar of the Leukemia and Lymphoma Society.
PY - 2008/7
Y1 - 2008/7
N2 - 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 α-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 α-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.
AB - 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 α-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 α-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.
KW - Aggresomes
KW - Apoptosis
KW - HDAC6
KW - Multiple myeloma
KW - Protein degradation
KW - α-Tubulin
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U2 - 10.1016/j.ymgme.2008.03.012
DO - 10.1016/j.ymgme.2008.03.012
M3 - Review article
C2 - 18472289
AN - SCOPUS:44949234487
SN - 1096-7192
VL - 94
SP - 283
EP - 286
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 3
ER -