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Schlafen-3 decreases cancer stem cell marker expression and autocrine/juxtacrine signaling in FOLFOX-resistant colon cancer cells.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2011 Aug; Vol. 301 (2), pp. G347-55. Date of Electronic Publication: 2011 May 19. - Publication Year :
- 2011
-
Abstract
- We have previously demonstrated that expression of the novel gene schlafen-3 (Slfn-3) correlates with intestinal epithelial cell differentiation (Patel VB, Yu Y, Das JK, Patel BB, Majumdar AP. Biochem Biophys Res Commun 388: 752-756, 2009). The present investigation was undertaken to examine whether Slfn-3 plays a role in regulating differentiation of FOLFOX-resistant (5-fluorouracil + oxaliplatin) colon cancer cells that are highly enriched in cancer stem cells (CSCs). Transfection of Slfn-3 in FOLFOX-resistant colon cancer HCT-116 cells resulted in increase of alkaline phosphatase activity, a marker of intestinal differentiation. Additionally, Slfn-3 transfection resulted in reduction of mRNA and protein levels of the CSC markers CD44, CD133, CD166, and aldehyde dehydrogenase 1 in both FOLFOX-resistant HCT-116 and HT-29 cells. This was accompanied by decreased formation of tumorosphere/colonosphere (an in vitro model of tumor growth) in stem cell medium and inhibition of expression of the chemotherapeutic drug transporter protein ABCG2. Additionally, Slfn-3 transfection of FOLFOX-resistant HCT-116 and HT-29 cells reduced Hoechst 33342 dye exclusion. Finally, Slfn-3 transfection inhibited the expression of transforming growth factor-α in both FOLFOX-resistant colon cancer cells, but stimulated apoptosis in response to additional FOLFOX treatment. In summary, our data demonstrate that Slfn-3 expression inhibits multiple characteristics of CSC-enriched, FOLFOX-resistant colon cancer cells, including induction of differentiation and reduction in tumorosphere/colonosphere formation, drug transporter activity, and autocrine stimulation of proliferation. Thus Slfn-3 expression may render colon CSCs more susceptible to cancer chemotherapeutics.
- Subjects :
- AC133 Antigen
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters metabolism
Aldehyde Dehydrogenase 1 Family
Antigens, CD metabolism
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Cell Adhesion Molecules, Neuronal metabolism
Cell Cycle Proteins physiology
Cell Differentiation genetics
Colonic Neoplasms genetics
ErbB Receptors metabolism
Fetal Proteins metabolism
Fluorouracil
Glycoproteins metabolism
HCT116 Cells
HT29 Cells
Humans
Hyaluronan Receptors metabolism
Isoenzymes metabolism
Leucovorin
Neoplasm Proteins metabolism
Organoplatinum Compounds
Peptides metabolism
Retinal Dehydrogenase metabolism
Signal Transduction genetics
Transfection
Transforming Growth Factor alpha metabolism
Autocrine Communication genetics
Cell Cycle Proteins genetics
Colonic Neoplasms drug therapy
Drug Resistance, Neoplasm genetics
Neoplastic Stem Cells metabolism
Proteins genetics
Proteins physiology
RNA, Messenger metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1547
- Volume :
- 301
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 21596996
- Full Text :
- https://doi.org/10.1152/ajpgi.00403.2010