Document Detail


ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets.
MedLine Citation:
PMID:  22887839     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.
Authors:
Yuchun Luo; Katiuscia Dallaglio; Ying Chen; William A Robinson; Steven E Robinson; Martin D McCarter; Jianbin Wang; Rene Gonzalez; David C Thompson; David A Norris; Dennis R Roop; Vasilis Vasiliou; Mayumi Fujita
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  30     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-21     Completed Date:  2013-01-31     Revised Date:  2013-12-06    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2100-13     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 AlphaMed Press.
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Dehydrogenase / antagonists & inhibitors,  genetics*
Aldehyde Oxidoreductases
Animals
Apoptosis / drug effects
Cell Transformation, Neoplastic / drug effects,  genetics*
Dacarbazine / analogs & derivatives,  pharmacology
Drug Resistance, Neoplasm / drug effects
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Silencing
Humans
Isoenzymes / antagonists & inhibitors,  genetics
Melanoma / enzymology,  genetics*,  pathology
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Transplantation
Neoplastic Stem Cells / drug effects*,  enzymology,  pathology
RNA, Small Interfering / genetics
Response Elements
Skin Neoplasms / enzymology,  genetics*,  pathology
Tretinoin / chemistry,  pharmacology
Grant Support
ID/Acronym/Agency:
CA125833/CA/NCI NIH HHS; EY11490/EY/NEI NIH HHS; EY17963/EY/NEI NIH HHS; P30 AR057212/AR/NIAMS NIH HHS; P30 CA046934/CA/NCI NIH HHS; R03 CA125833/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Isoenzymes; 0/RNA, Small Interfering; 5688UTC01R/Tretinoin; 7GR28W0FJI/Dacarbazine; 85622-93-1/temozolomide; EC 1.2.-/Aldehyde Oxidoreductases; EC 1.2.1.3/ALDH1A1 protein, human; EC 1.2.1.3/Aldehyde Dehydrogenase; EC 1.2.1.5/aldehyde dehydrogenase (NAD(P)+)
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