259
Views
27
CrossRef citations to date
0
Altmetric
ORIGINAL ARTICLEPreclinical Therapeutics

Invasive Ability of Human Renal Cell Carcinoma Cell Line Caki-2 Is Accelerated by Gamma-Aminobutyric Acid, via Sustained Activation of ERK1/2 Inducible Matrix Metalloproteinases

, M.D., Ph.D., , M.D., Ph.D., , M.D., Ph.D., , , M.D., Ph.D., , M.D., , Ph.D. & , M.D. show all
Pages 574-583 | Published online: 11 Jun 2009
 

Abstract

Gamma-aminobutyric acid (GABA) was first discovered as an inhibitory neurotransmitter in the central nervous system (CNS) and has been reported to have a variety of functions, including regulation of cell division, cell differentiation and maturation, and to be involved in the development of certain cancers outside the CNS. In the present study, using the human renal cell carcinoma cell line Caki-2, we demonstrated that GABA stimulation significantly increased the expression of MMP-2 and -9 and subsequently increased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with GABA. It was found that GABA stimulation promoted the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. ERK1/2 phosphorylation was sustained for up to 12 h, while phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated GABA-induced MMP-9 expression and that both PD98059 and MMP inhibitors attenuated the GABA-induced invasive activity of Caki-2 cells. Moreover, data obtained by depletion of the MEK/ERK pathway using interfering RNA transfection of Caki-2 cells clearly corroborated the above results, as both MMP-9 expression and GABA-induced invasive ability were decreased significantly. We also demonstrated that the GABA-induced increase in invasive ability via ERK1/2 up-regulation was mediated mainly through the GABA-B receptor. These results indicate that GABA stimulation promotes cancer cell invasion and that the effect is partly due to ERK1/2-dependent up-regulation of MMPs.

Abbreviations
BSA=

bovine serum albumin

BMI=

bicuculline methiodide

ERK1/2=

extracellular signal regulated kinase.

GABA=

gamma-aminobutyric acid

JNK=

c-Jun N-terminal kinase

MAPK=

mitogen-activated protein kinase

MMP=

matrix metalloproteinase

p38=

p38 mitogen-activated protein kinase

RCC=

renal cell carcinoma

Abbreviations
BSA=

bovine serum albumin

BMI=

bicuculline methiodide

ERK1/2=

extracellular signal regulated kinase.

GABA=

gamma-aminobutyric acid

JNK=

c-Jun N-terminal kinase

MAPK=

mitogen-activated protein kinase

MMP=

matrix metalloproteinase

p38=

p38 mitogen-activated protein kinase

RCC=

renal cell carcinoma

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.