PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1

Ramanjaneya V. Mula; Vandanajay Bhatia; Miriam Falzon

doi:10.1016/j.canlet.2010.06.009

PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1

Ramanjaneya V. Mula, Vandanajay Bhatia, Miriam Falzon

Pharmacology & Toxicology

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines. Rac1 GTPase enhances colon cancer cell migration and invasion. Here we report a positive correlation between PTHrP expression and Rac1 activity in LoVo (human colon cancer) cells. The positive effects of PTHrP on Rac1 activity and on cell migration and invasion are mediated via the guanine nucleotide exchange factor Tiam1. Knockdown of integrin α6β4, which is upregulated by PTHrP, negates the PTHrP-mediated increase in Rac1 activation. Integrin α6β4 signals synergistically with growth factor receptors to activate the phosphatidylinositol 3-kinase (PI3-K) pathway. Chemical inhibition of PI3-K negates the PTHrP-mediated effects on Tiam1 and Rac1 activity. Tumors from PTHrP-overexpressing LoVo cells also show increased expression of Tiam1. Taken together, these observations provide evidence of a link between PTHrP and Rac1 activity through integrin α6β4, resulting in enhanced cell migration and invasion. Targeting PTHrP production in colon cancer may thus prove therapeutically beneficial.

Original language	English (US)
Pages (from-to)	119-127
Number of pages	9
Journal	Cancer Letters
Volume	298
Issue number	1
DOIs	https://doi.org/10.1016/j.canlet.2010.06.009
State	Published - Dec 2010

Keywords

Integrin α6β4
PTHrP
Phosphatidylinositol 3-kinase
Rac1
Tiam1

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2010.06.009

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title = "PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1",

abstract = "Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines. Rac1 GTPase enhances colon cancer cell migration and invasion. Here we report a positive correlation between PTHrP expression and Rac1 activity in LoVo (human colon cancer) cells. The positive effects of PTHrP on Rac1 activity and on cell migration and invasion are mediated via the guanine nucleotide exchange factor Tiam1. Knockdown of integrin α6β4, which is upregulated by PTHrP, negates the PTHrP-mediated increase in Rac1 activation. Integrin α6β4 signals synergistically with growth factor receptors to activate the phosphatidylinositol 3-kinase (PI3-K) pathway. Chemical inhibition of PI3-K negates the PTHrP-mediated effects on Tiam1 and Rac1 activity. Tumors from PTHrP-overexpressing LoVo cells also show increased expression of Tiam1. Taken together, these observations provide evidence of a link between PTHrP and Rac1 activity through integrin α6β4, resulting in enhanced cell migration and invasion. Targeting PTHrP production in colon cancer may thus prove therapeutically beneficial.",

keywords = "Integrin α6β4, PTHrP, Phosphatidylinositol 3-kinase, Rac1, Tiam1",

author = "Mula, {Ramanjaneya V.} and Vandanajay Bhatia and Miriam Falzon",

note = "Funding Information: This work was supported by NIH Grant DK035608 .",

year = "2010",

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doi = "10.1016/j.canlet.2010.06.009",

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T1 - PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1

AU - Mula, Ramanjaneya V.

AU - Bhatia, Vandanajay

AU - Falzon, Miriam

N1 - Funding Information: This work was supported by NIH Grant DK035608 .

PY - 2010/12

Y1 - 2010/12

N2 - Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines. Rac1 GTPase enhances colon cancer cell migration and invasion. Here we report a positive correlation between PTHrP expression and Rac1 activity in LoVo (human colon cancer) cells. The positive effects of PTHrP on Rac1 activity and on cell migration and invasion are mediated via the guanine nucleotide exchange factor Tiam1. Knockdown of integrin α6β4, which is upregulated by PTHrP, negates the PTHrP-mediated increase in Rac1 activation. Integrin α6β4 signals synergistically with growth factor receptors to activate the phosphatidylinositol 3-kinase (PI3-K) pathway. Chemical inhibition of PI3-K negates the PTHrP-mediated effects on Tiam1 and Rac1 activity. Tumors from PTHrP-overexpressing LoVo cells also show increased expression of Tiam1. Taken together, these observations provide evidence of a link between PTHrP and Rac1 activity through integrin α6β4, resulting in enhanced cell migration and invasion. Targeting PTHrP production in colon cancer may thus prove therapeutically beneficial.

AB - Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines. Rac1 GTPase enhances colon cancer cell migration and invasion. Here we report a positive correlation between PTHrP expression and Rac1 activity in LoVo (human colon cancer) cells. The positive effects of PTHrP on Rac1 activity and on cell migration and invasion are mediated via the guanine nucleotide exchange factor Tiam1. Knockdown of integrin α6β4, which is upregulated by PTHrP, negates the PTHrP-mediated increase in Rac1 activation. Integrin α6β4 signals synergistically with growth factor receptors to activate the phosphatidylinositol 3-kinase (PI3-K) pathway. Chemical inhibition of PI3-K negates the PTHrP-mediated effects on Tiam1 and Rac1 activity. Tumors from PTHrP-overexpressing LoVo cells also show increased expression of Tiam1. Taken together, these observations provide evidence of a link between PTHrP and Rac1 activity through integrin α6β4, resulting in enhanced cell migration and invasion. Targeting PTHrP production in colon cancer may thus prove therapeutically beneficial.

KW - Integrin α6β4

KW - PTHrP

KW - Phosphatidylinositol 3-kinase

KW - Rac1

KW - Tiam1

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PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1

Abstract

Keywords

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