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Role of the Aggresome Pathway in Cancer: Targeting Histone Deacetylase 6–Dependent Protein Degradation

¹ Division of Hematology-Oncology, Mattel Children's Hospital and ² Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and ³ Division of Biology, California Institute of Technology, Pasadena, California

Requests for reprints: Kathleen M. Sakamoto, Division of Hematology-Oncology, Mattel Children's Hospital University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095-1752. Phone: 310-794-7007; Fax: 310-206-8089; E-mail: kms{at}ucla.edu.

Key Words: aggresomes • protein degradation • cancer • HDAC6 • ubiquitination • apoptosis

Misfolded or aggregated proteins have two fates: they are either refolded with the help of chaperones or degraded by the proteasome. Cells also have an alternative pathway that involves intracellular "storage bins" for misfolded intracellular proteins known as aggresomes. Aggresomes recruit motor proteins that transport misfolded or aggregated proteins to chaperones and proteasomes for subsequent destruction. There is emerging evidence that inhibiting the aggresome pathway leads to accumulation of misfolded proteins and apoptosis in tumor cells through autophagy. We discuss the role of aggresomes in cancer and the potential to target this pathway for therapy. [Cancer Res 2008;68(8):2557–60]