Insulin-like growth factors are more effective than progastrin in reversing proapoptotic effects of curcumin: critical role of p38MAPK.
Progastrin and insulin-like growth factors (IGFs) stimulate hyperproliferation of intestinal epithelial cells (IECs) via endocrine/paracrine routes; hyperproliferation is a known risk factor for colon carcinogenesis. In the present study, inhibitory potency of curcumin in the presence or absence of progastrin and/or IGF-II was examined. Progastrin and IGF-II significantly increased proliferation of an immortalized IEC cell line, IEC-18, whereas curcumin decreased the proliferation in a dose-dependent manner. IGF-II was significantly more effective than progastrin in reversing antiproliferative effects of curcumin and reversed proapoptotic effects of curcumin by >80%; progastrin was relatively ineffective toward reversing proapoptotic effects of curcumin. IEC-18 clones were generated to overexpress either progastrin (IEC-PG) or hIGF-II (IEC-IGF). Proliferation of IEC-PG and IEC-IGF clones was increased, compared with that of control clones. Curcumin significantly reduced proliferation of IEC-PG, but not IEC-IGF, clones. Similarly, a human colon cancer cell line, Caco-2 (which expresses autocrine IGF-II), was relatively resistant to inhibitory effects of curcumin. However, Caco-2 cells treated with anti-IGF-II-antibodies were rendered sensitive to inhibitory effects of curcumin. Significant differences in inhibitory potency of curcumin against PG- vs. IGF-II-stimulated growth of IEC-18 cells were not reflected by differences in curcumin-mediated inhibition of activated (phosphorylated) ERKs/IKK(alpha/beta)/p65NF-kappaB and c-Src in wild-type (wt)IEC-18 cells, in response to the two growth factors. Surprisingly, curcumin was almost ineffective in reducing IGF-II-stimulated activation of p38MAPK but significantly reduced progastrin-stimulated phosphorylation of p38. Treatment with a p38MAPK inhibitor resulted in loss of protective effects of IGF-II against inhibitory effects of curcumin. These novel findings suggest that growth factor profile of patients and tumors may dictate inhibitory potency of curcumin and that combination of curcumin + p38MAPK inhibitor may be required for reducing hyperproliferative or tumorigenic response of IECs to endocrine and autocrine IGFs.
Singh
Pomila
P
Dept. of Neuroscience and Cell Biology, Univ. of Texas Medical Branch, 10.104 Medical Research Bldg., 301 Univ. Blvd., Route 1043, Galveston, TX 77555-1043, USA. posingh@utmb.edu
Sarkar
Shubhashish
S
Umar
Shahid
S
Rengifo-Cam
William
W
Singh
Amar P
AP
Wood
Thomas G
TG
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D018938:Caco-2 Cells; D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005755:Gastrins / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007082:Ileum / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013002:Somatomedins / Q000235:genetics / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019061:src-Family Kinases
D000906:Antibodies; D005755:Gastrins; D007093:Imidazoles; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011498:Protein Precursors; D011725:Pyridines; D013002:Somatomedins; D051996:Transcription Factor RelA; C013706:big gastrin; D007335:Insulin-Like Growth Factor II; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051550:I-kappa B Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; D003474:Curcumin; C093642:SB 203580; D002166:Camptothecin