Schlafen-3 decreases cancer stem cell marker expression and autocrine/juxtacrine signaling in FOLFOX-resistant colon cancer cells.

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.

• Authors: Phil-Sun Oh, Vaishali B Patel, Matthew A Sanders, Shailender S Kanwar, Yingjie Yu, Jyoti Nautiyal, Bhaumik B Patel, Adhip P N Majumdar
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 301 Issue 2 Pg. G347-55 (Aug 2011) ISSN: 1522-1547 [Electronic] United States
• PMID: 21596996 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ABCG2 protein, human
• AC133 Antigen
• ALCAM protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antigens, CD
• CD44 protein, human
• Cell Adhesion Molecules, Neuronal
• Cell Cycle Proteins
• Fetal Proteins
• Glycoproteins
• Hyaluronan Receptors
• Isoenzymes
• Neoplasm Proteins
• Organoplatinum Compounds
• PROM1 protein, human
• Peptides
• Proteins
• RNA, Messenger
• Schlafen-3 protein, human
• Transforming Growth Factor alpha
• Aldehyde Dehydrogenase 1 Family
• ALDH1A1 protein, human
• Retinal Dehydrogenase
• ErbB Receptors
• Leucovorin
• Fluorouracil

Topics

• 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
• Autocrine Communication (genetics)
• Cell Adhesion Molecules, Neuronal (metabolism)
• Cell Cycle Proteins (genetics, physiology)
• Cell Differentiation (genetics)
• Colonic Neoplasms (drug therapy, genetics)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (metabolism)
• Fetal Proteins (metabolism)
• Fluorouracil
• Glycoproteins (metabolism)
• HCT116 Cells
• HT29 Cells
• Humans
• Hyaluronan Receptors (metabolism)
• Isoenzymes (metabolism)
• Leucovorin
• Neoplasm Proteins (metabolism)
• Neoplastic Stem Cells (metabolism)
• Organoplatinum Compounds
• Peptides (metabolism)
• Proteins (genetics, physiology)
• RNA, Messenger (metabolism)
• Retinal Dehydrogenase (metabolism)
• Signal Transduction (genetics)
• Transfection
• Transforming Growth Factor alpha (metabolism)