Hohla, Florian and Buchholz, Stefan and Schally, Andrew V. and Seitz, Stefan and Rick, Ferenc G. and Szalontay, Luca and Varga, Jozsef L. and Zarandi, Marta and Halmos, Gabor and Vidaurre, Irving and Krishan, Awtar and Kurtoglu, Metin and Chandna, Sudhir and Aigner, Elmar and Datz, Christian (2009) GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells. CELL CYCLE, 8 (19). pp. 3149-3156. ISSN 1538-4101, 1551-4005
Full text not available from this repository. (Request a copy)Abstract
We investigated the mechanisms of inhibitory effect of growth hormone-releasing hormone (GHRH) antagonist JMR-132 on the growth of HT29, HCT-116 and HCT-15 human colon cancer cells in vitro and in vivo. High-affinity binding sites for GHRH and mRNA for GHRH and splice variant-1 (SV1) of the GHRH receptor were found in all three cell lines tested. Proliferation of HT-29, HCT-116 and HCT-15 cells was significantly inhibited in vitro by JMR-132. Time course studies revealed that the treatment of human HCT-116 colon cancer cells with 10 mu M GHRH antagonist JMR-132 causes a significant DNA damage as shown by an increase in olive tail moment (OTM) and loss of inner mitochondrial membrane potential (Delta psi m). Western blotting demonstrated a time-dependent increase in protein levels of phospho-p53 (Ser46), Bax, cleaved caspase-9, -3, cleavage of poly(ADP-ribose) polymerase (PARP) and a decrease in Bcl-2 levels. An augmentation in cell cycle checkpoint protein (p21Waf1/Cip1) was accompanied by a cell cycle arrest in S-phase. DNA fragmentation visualized by the comet assay and the number of apoptotic cells increased time dependently as determined by flow cytometric annexinV and PI staining assays. In vivo, JMR-132 decreased the volume of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic mice up to 75% (p < 0.05) and extended tumor doubling time (p < 0.001). Our observations suggest that GHRH antagonist JMR-132 exerts its antiproliferative effect on experimental colon cancer cells through p(21Waf1/Cip1) mediated S-phase arrest along with apoptosis involving the intrinsic pathway.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HORMONE-RELEASING-HORMONE; HUMAN PROSTATE-CANCER; SPLICE VARIANTS; GROWTH; EXPRESSION; RECEPTOR; DEATH; P53; CHECKPOINTS; INHIBITION; GHRH antagonist; mitochondrial membrane potential; cell cycle arrest; apoptosis; p21; DNA damage; colon cancer |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Frauenheilkunde und Geburtshilfe (Schwerpunkt Frauenheilkunde) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Sep 2020 12:28 |
| Last Modified: | 03 Sep 2020 12:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/28308 |
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