Restored expression of the atypical heat shock protein H11/HspB8 inhibits the growth of genetically diverse melanoma tumors through activation of novel TAK1-dependent death pathways
Open Access
- 16 August 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 3 (8), e371
- https://doi.org/10.1038/cddis.2012.108
Abstract
Melanoma is an aggressive and drug-resistant cancer in need of improved therapeutic strategies. Restored expression of transcriptionally silenced genes is a potential approach, but it is limited by the genetic diversity of the melanoma tumors. The atypical heat shock protein H11/HspB8 has kinase activity and is silenced in melanoma through aberrant DNA methylation. We report that its restored expression induces the death of genetically diverse melanoma lines and inhibits tumor growth through the activation of novel TAK1-dependent death pathways. These include (i) caspase-1 activation independent of the inflammasome through upregulation of apoptosis-associated speck-like protein containing a CARD (ASC), (ii) Beclin-1 upregulation through phosphorylation of mammalian target of rapamycin (mTOR) at S2481 and (iii) apoptosis caused by caspase-1-mediated Beclin-1 cleavage. These data extend current understanding of cell death-associated functions, underscore the strong therapeutic promise of H11/HspB8 and identify TAK1 as a potential intervention target in melanoma.Keywords
This publication has 35 references indexed in Scilit:
- The mTOR Signalling Pathway in Human CancerInternational Journal of Molecular Sciences, 2012
- Influence of co-down-regulation of caspase-3 and caspase-7 by siRNAs on sodium butyrate-induced apoptotic cell death of Chinese hamster ovary cells producing thrombopoietinMetabolic Engineering, 2007
- Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-β-activated kinase 1Oncogene, 2006
- Ras-Associated Protein-1 Regulates Extracellular Signal-Regulated Kinase Activation and Migration in Melanoma Cells: Two Processes Important to Melanoma Tumorigenesis and MetastasisCancer Research, 2006
- Spontaneous apoptosis of melanotic and amelanotic melanoma cells in different phases of cell cycle: relation to tumor growth.2006
- TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivoGenes & Development, 2005
- Activation of c-Jun N-terminal kinase (JNK) pathway by HSV-1 immediate early protein ICP0Experimental Cell Research, 2005
- Caspase-1 Activates Nuclear Factor of the κ-Enhancer in B Cells Independently of Its Enzymatic ActivityJournal of Biological Chemistry, 2004
- Forced Expression of the H11 Heat Shock Protein Can Be Regulated by DNA Methylation and Trigger Apoptosis in Human CellsOnline Journal of Public Health Informatics, 2003
- A Novel Human Gene Similar to the Protein Kinase (PK) Coding Domain of the Large Subunit of Herpes Simplex Virus Type 2 Ribonucleotide Reductase (ICP10) Codes for a Serine-Threonine PK and Is Expressed in Melanoma CellsOnline Journal of Public Health Informatics, 2000