pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1).
Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr(421)) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr(421)-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr(421)-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr(421)-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr(421)-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr(421)-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr(421)-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr(421)-CTTN expression.
Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America.
Vijayababu M
VM
Radhakrishnan
Department of Nutritional Sciences, Tucson, Arizona, United States of America.
Pawel
P
Kojs
Arizona Cancer Center, Tucson, Arizona, United States of America.
Gavin
G
Young
Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America.
Rajalakshmy
R
Ramalingam
Arizona Cancer Center, Tucson, Arizona, United States of America ; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, United States of America.
Bhumasamudram
B
Jagadish
Arizona Cancer Center, Tucson, Arizona, United States of America ; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, United States of America.
Eugene A
EA
Mash
Arizona Cancer Center, Tucson, Arizona, United States of America.
Jesse D
JD
Martinez
Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America.
Fayez K
FK
Ghishan
Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America ; Department of Immunobiology, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America.
Pawel R
PR
Kiela
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D051177:Catenins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D003474:Curcumin / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000378:metabolism*; D000095002:Delta Catenin
D000970:Antineoplastic Agents; D051177:Catenins; D051356:Cortactin; D014443:Tyrosine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D003474:Curcumin; D000095002:Delta Catenin; C000722347:CTNND1 protein, human