Characterization of RhoA-mediated Chemoresistance in Gastric Cancer Cells
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Purpose: RhoA is a critical transducer of extracellular signals, which leads to organization of actin cytoskeleton, motility, adhesion and gene regulation. The present study aimed to explore whether RhoA influences the susceptibility of gastric cancer cells to chemotherapeutic drugs. Materials and Methods: SNU638 cells were transfected with a mock vector (pcDNA3.1), RhoA (pcDNA/RhoA), or constitutively active RhoA (pcDNA/caRhoA). MTT assay and Western blot analysis were performed to study the growth response to several chemotherapeutic drugs in the gastric cancer cell line, SNU638, with different RhoA levels. Results: RhoA significantly enhanced the resistance to lovastatin, 5-FU, taxol and vincristine, but did not affect the sensitivity to cisplatin or etoposide in SNU638. In the Western blot analysis, RhoA decreased the PARP cleavage, which was accompanied by a concurrent reductionin cell death. The gene expression profile after a cDNA microarray analysis demonstrated that RhoA was associated with the differential expression of 19 genes, including those involved in anti-oxidant defense, glucose metabolism, anti-apoptosis and protein turnover. Conclusion: Gastric cancer cells with a high expression of RhoA could be resistant to chemotherapeutic drugs, such as taxol or vincristine, implying that treatment strategies aimed at inactivation of RhoA might be promising for improving the efficacy of these chemotherapeutic drugs.
Abstract
Purpose: RhoA is a critical transducer of extracellular signals, which leads to organization of actin cytoskeleton, motility, adhesion and gene regulation. The present study aimed to explore whether RhoA influences the susceptibility of gastric cancer cells to chemotherapeutic drugs. Materials and Methods: SNU638 cells were transfected with a mock vector (pcDNA3.1), RhoA (pcDNA/RhoA), or constitutively active RhoA (pcDNA/caRhoA). MTT assay and Western blot analysis were performed to study the growth response to several chemotherapeutic drugs in the gastric cancer cell line, SNU638, with different RhoA levels. Results: RhoA significantly enhanced the resistance to lovastatin, 5-FU, taxol and vincristine, but did not affect the sensitivity to cisplatin or etoposide in SNU638. In the Western blot analysis, RhoA decreased the PARP cleavage, which was accompanied by a concurrent reductionin cell death. The gene expression profile after a cDNA microarray analysis demonstrated that RhoA was associated with the differential expression of 19 genes, including those involved in anti-oxidant defense, glucose metabolism, anti-apoptosis and protein turnover. Conclusion: Gastric cancer cells with a high expression of RhoA could be resistant to chemotherapeutic drugs, such as taxol or vincristine, implying that treatment strategies aimed at inactivation of RhoA might be promising for improving the efficacy of these chemotherapeutic drugs.
참고문헌 (23)
- "Activation of Rac1, RhoA, and mitogen-activated proteinkinases is required for Ras transformation.", 15, pp.6443~53 (1995)
- "Inactivation of the smallGTP binding protein Rho induces multinucleate cell formationand apoptosis in murine T lymphoma EL4", 156, pp.4146~53 (1996)
- "Tumorigenic activity of rho genes from Aplysiacalifornica", 8, pp.1285~92 (1993)
- "Critical role of Rho in cell transformationby oncogenic Ras", 10, pp.2289~96 (1995)
- "Overexpression of smallGTP-binding protein RhoA promotes invasion of tumor cells", 59, pp.2004~10 (1999)
- "Examination of human tumors for rhoA mutations", 9, pp.189~94 (1994)
- "Inactivationof the small GTPase Rho disrupts cellular attachmentand induces adhesion-dependent and adhesion-independentapoptosis", 15, pp.2179~89 (1997)
- "Induction of apoptosis by rhoin NIH 3T3 cells requires two complementary signals Ceramides function as a progression factor for apoptosis", pp.2657~65 (1995)
- "Antiapoptotic signaling inLNCaP prostate cancer cells: a survival signaling pathwayindependent of phosphatidylinositol 3'-kinase and Akt", proteinkinase B, 1999, pp.59, 1449~53
- "The phosphatidylinositol3'-kinase pathway is a dominant growth factoractivatedcell survival pathway in LNCaP human gastric carcinomacells", 59, pp.2891~7 (1999)
- "Identification of genes with differential expression in acquireddrug-resistant gastric cancer cells using high-density oligonucleotidemicroarrays", 10, pp.272~84 (2004)
- "Influence of the proto-oncogene c-foson cisplatin sensitivity", 59, pp.337~45 (2000)
- "Heat-shock protein expression in cisplatinsensitiveand -resistant human tumor cells", 67, pp.800~7 (1996)
- "Enhancementof sensitivity of urinary bladder tumor cells to cisplatinby c-myc antisense oligonucleotide", 74, pp.2546~54 (1994)
- "BCL-2family protein expression and platinum drug resistance inovarian carcinoma", 82, pp.436~40 (2000)
- "Lovastatin-induced E2F-1 modulationand its effect on prostate cancer cell death", 22, pp.1727~31 (2001)
- "Vascular endothelial growth factor (VEGF) upregulatesBCL-2 and inhibits apoptosis in human and murine mammaryadenocarcinoma cells", 85, pp.273~8 (2001)
- "Epidermalgrowth factor receptor-dependent Akt activation by oxidativestress enhances cell survival", 275, pp.14624~31 (2000)
- "The drug resistance-related protein LRPis the human major vault protein", 1, pp.578~82 (1995)
- "Expression of MDR1 and GST-pi in human softtissue sarcomas:relation to drug resistance and biologicalaggressiveness", 3, pp.63~9 (1992)
- "From bench to clinic with apoptosis-basedtherapeutic agents", 407, pp.810~6 (2000)
- "Regulation of the mevalonate pathway", 343, pp.425~30 (1990)
- "BaldwinAS Jr. NF-kappaB antiapoptosis: induction of TRAF1 andTRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation", 281, pp.1680~3 (1998)