title: RhoGDI2 confers gastric cancer cells resistance against cisplatin-induced apoptosis by upregulation of Bcl-2 expression.
abstract: Rho GDP dissociation inhibitor (RhoGDI)2 has been identified as a regulator of Rho family GTPase. Recently, we suggested that RhoGDI2 could promote tumor growth and malignant progression in gastric cancer. In this study, we demonstrate that RhoGDI2 contributes to another important feature of aggressive cancers, i.e., resistance to chemotherapeutic agents such as cisplatin. Forced expression of RhoGDI2 attenuated cisplatin-induced apoptosis, whereas RhoGDI2 depletion showed opposite effects in vitro. Moreover, the increased anti-apoptotic effect of RhoGDI2 on cisplatin was further validated in RhoGDI2-overexpressing SNU-484 xenograft model in nude mice. Furthermore, we identified Bcl-2 as a major determinant of RhoGDI2-mediated cisplatin resistance in gastric cancer cells. Depletion of Bcl-2 expression significantly increased cisplatin-induced apoptosis in RhoGDI2-overexpressing gastric cancer cells, whereas overexpression of Bcl-2 blocked cisplatin-induced apoptosis in RhoGDI2-depleted gastric cancer cells. Overall, these findings establish RhoGDI2 as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk in gastric cancer.
authors.affiliation: Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Hee Jun
authors.initials: HJ
authors.lastname: Cho
authors.forename: Kyoung Eun
authors.initials: KE
authors.lastname: Baek
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Park
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Kim
authors.forename: In-Koo
authors.initials: IK
authors.lastname: Nam
authors.forename: Yeong-Lim
authors.initials: YL
authors.lastname: Choi
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Im
authors.forename: Jungil
authors.initials: J
authors.lastname: Choi
authors.forename: Jinhyun
authors.initials: J
authors.lastname: Ryu
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Chang Won
authors.initials: CW
authors.lastname: Lee
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Jiyun
authors.initials: J
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
chemical_list: C569638:ARHGDIA protein, human; C569658:ARHGDIB protein, human; D000970:Antineoplastic Agents; D020730:Guanine Nucleotide Dissociation Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D005047:Etoposide; D019311:Staurosporine; D002945:Cisplatin