PTHrP promotes colon cancer cell migration and invasion in an integrin α6β4-dependent manner through activation of Rac1.
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.
Mula
Ramanjaneya V
RV
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
Bhatia
Vandanajay
V
Falzon
Miriam
M
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D039161:Integrin alpha6beta4; D044162:Parathyroid Hormone-Related Protein; C107953:RAC1 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D020830:rac1 GTP-Binding Protein