Gene expression analysis of HCT116 colon tumor-derived cells treated with the polyamine analog PG-11047.
BACKGROUND
The conformationally restricted polyamine analog PG-11047 has significant growth inhibitory activity against prostate and lung cancer cell lines and is currently under evaluation in several clinical trials, both alone and in combination with other drugs, for the treatment of relapsed or refractory cancer. The objective of this study was to identify the molecular signature of genes responsive to PG-11047 treatment and the biochemical effects of this drug in the HCT116 colon cancer cell line.


METHODS
Gene expression analysis was performed using Affymetrix GeneChip human genome U133 Plus 2.0 arrays. Changes in protein expression were evaluated using 2D polyacrylamide gels followed by LCMS/MS.


RESULTS
Treatment of cells with PG-11047 at concentrations ranging from 0.1 to 10 microM caused inhibition of cell growth. The activity of PG-11047 was found to correlate with its transcriptional effects on cell cycle control, focal adhesion, adherent and gap junction genes, MAPK-, Wnt- and, TGF-beta signaling pathways, transport and DNA/RNA transcription factor genes. PG-11047 caused depletion of polyamine pools. Proteomics analysis showed that PG-11047 restricts the modification of eukaryotic translation initiation factor 5A (eIF5A), resulting in suppression of general protein synthesis in PG-11047-treated cells.


CONCLUSIONS
These data show that PG-11047 has a broad spectrum of anticancer activity in colon cancer cells.
Ignatenko
Natalia A
NA
Department of Cell Biology and Anatomy, Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA. nignatenko@azcc.arizona.edu
Yerushalmi
Hagit F
HF
Pandey
Ritu
R
Kachel
Karen L
KL
Stringer
David E
DE
Marton
Laurence J
LJ
Gerner
Eugene W
EW
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects*; D052138:Genes, Neoplasm / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
C415967:(N(1),N(12))bis(ethyl)-6,7-dehydrospermine; D000970:Antineoplastic Agents; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D013096:Spermine