pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: Involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1)

Vijayababu M. Radhakrishnan, Pawel Kojs, Gavin Young, Rajalakshmy Ramalingam, Bhumasamudram Jagadish, Eugene A Mash, Jesse D Martinez, Fayez K Ghishan, Pawel R Kiela

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Abstract

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 pTyr421-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 pTyr421-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 pTyr421-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr421-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 pTyr421-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 pTyr421-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr421-CTTN expression.

Original languageEnglish (US)
Article numbere85796
JournalPLoS One
Volume9
Issue number1
DOIs
StatePublished - Jan 22 2014

Fingerprint

Cortactin
Non-Receptor Type 1 Protein Tyrosine Phosphatase
protein-tyrosine-phosphatase
Curcumin
curcumin
colorectal neoplasms
Colonic Neoplasms
cell movement
cell invasion
dephosphorylation
cells
neoplasms
tyrosine
HCT116 Cells
biotinylation
Cell Movement
Tumors
HT29 Cells
therapeutics
adenocarcinoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin : Involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1). / Radhakrishnan, Vijayababu M.; Kojs, Pawel; Young, Gavin; Ramalingam, Rajalakshmy; Jagadish, Bhumasamudram; Mash, Eugene A; Martinez, Jesse D; Ghishan, Fayez K; Kiela, Pawel R.

In: PLoS One, Vol. 9, No. 1, e85796, 22.01.2014.

Research output: Contribution to journalArticle

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abstract = "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 pTyr421-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 pTyr421-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 pTyr421-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr421-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 pTyr421-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 pTyr421-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr421-CTTN expression.",
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AU - Radhakrishnan, Vijayababu M.

AU - Kojs, Pawel

AU - Young, Gavin

AU - Ramalingam, Rajalakshmy

AU - Jagadish, Bhumasamudram

AU - Mash, Eugene A

AU - Martinez, Jesse D

AU - Ghishan, Fayez K

AU - Kiela, Pawel R

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