Exp Mol Med.  2004 Dec;36(6):557-562.

p21Cip/WAF1 activation is an important factor for the ERK pathway dependent anti-proliferation of colorectal cancer cells

• Park KS
• Jeon SH
• Oh JW
• Choi KY

Abstract

p21Cip/WAF1, an important regulator of cell proliferation, is induced by both p53- and extracellular signal regulated kinase (ERK) pathways. The induction of p21Cip/WAF1 occurs by prolonged activation of the ERKs caused by extracellular stimuli, such as zinc. However, not all the cells appeared to respond to ERK pathway dependent p21Cip/WAF1 induction. Here we investigated the cause of such difference using colorectal cancer cells. p21Cip/WAF1 induction and concomitant reduction of bromodeoxyuridine (BrdU) incorporation were observed by zinc treatment within HT-29 and DLD-1. However, HCT-116 cells with high endogenous p21Cip/WAF1 levels did not show any additional increment of p21Cip/WAF1 levels by zinc treatment and did maintain high BrdU incorporation level. The p21Cip/WAF1 induction by zinc depended upon prolonged activation of extracellular signal regulated kinase (ERK) was not observed in HCT-116 cells. The percentage of BrdU positive cells was 50% higher in p21Cip/WAF1 -/- HCT-116 cells compared to p21Cip/WAF1 +/+ HCT- 116 cells, and no cells induced p21Cip/WAF1 incorporated BrdU in its nucleus, yet confirming the importance of p21Cip/WAF1 induction in anti- proliferation. These results again support that p21Cip/WAF1 induction is a determinant in the regulation of colonic proliferation by the ERK pathway.

Keyword

anti-proliferation; colorectal cancer; ERK; MAP kinase; p21Cip/WAF1; Zinc

MeSH Terms

Bromodeoxyuridine/metabolism
Cell Cycle Proteins/*metabolism
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms/enzymology/*metabolism
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases/metabolism/*physiology
Flavonoids/pharmacology
Humans
Protein Kinase Inhibitors/pharmacology
Research Support, Non-U.S. Gov't
Signal Transduction/drug effects
Zinc/pharmacology