Extracellular zinc stimulates ERK-dependent activation of p21(Cip/WAF1) and inhibits proliferation of colorectal cancer cells.
Zinc is an important trace element in the body and is involved in both the proliferation and growth arrest of many kinds of cells including colorectal epithelial cells. The aim of this study was to identify the molecular mechanism of the growth regulation of colorectal cancer cells by extracellular zinc. Zinc-stimulated activation of the mitogen-activated protein kinase (MAPK) cascade was measured by immunoblotting and Elk-1 dependent trans-reporter gene expression, and zinc-stimulated p21(Cip/WAF1) activation by immunoblotting, Northern blot analysis and immunochemistry. Cell proliferation was measured by thymidine and bromodeoxyuridine (BrdU) incorporation. By treating colorectal cancer cells with 100 microM ZnCl2, MAPKs were activated in two different phases, the initial weak activation occurred within 5 min and this was followed by a stronger and more prolonged activation. Zinc concomitantly activated Raf-1-MEK-MAPK kinases, and induced Elk-1 dependent trans-reporter gene expression. Prolonged activation of MAPKs by 100 microM of ZnCl2 resulted in the induction and nuclear localization of p21(Cip/WAF1) and was related to the inhibition of both thymidine and BrdU incorporations. These results not only suggest the presence of a mechanism for p21(Cip/WAF1) dependent negative regulation of colorectal cancer cell growth by zinc but also suggest potential usage of zinc to control the growth of colorectal cancer cells.
Park
Ki-Sook
KS
Department of Biotechnology, College of Engineering, Yonsei University, Seoul, 120-754 Korea.
Ahn
Yongho
Y
Kim
Jin-Ah
JA
Yun
Mi-Sun
MS
Seong
Baik L
BL
Choi
Kang-Yell
KY
D002455:Cell Division / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017967:Zinc Compounds / Q000494:pharmacology
C493956:CDKN1A protein, human; D002712:Chlorides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D012333:RNA, Messenger; D017967:Zinc Compounds; C016837:zinc chloride; D020928:Mitogen-Activated Protein Kinases