The transcription factor GCF2 is an upstream repressor of the small GTPAse RhoA, regulating membrane protein trafficking, sensitivity to doxorubicin, and resistance to cisplatin.

Molecular Pharmaceutics
Ding-Wu ShenMichael M Gottesman

Abstract

Our aim was to explore the involvement of the transcriptional suppressor GCF2 in silencing RhoA, disorganization of the cytoskeleton, mislocalization of MRP1, and sensitivity to anticancer agents as an upstream gene target in cancer therapy. Increased expression of GCF2 was found in human cisplatin-resistant cells, and overexpression in GCF2-transfected cells results in loss of RhoA expression and disruption of the actin/filamin network. In consequence, the membrane transporter MRP1 was internalized from the cell surface into the cytoplasm, rendering cells sensitive to doxorubicin by more than 10-fold due to increased accumulation of doxorubicin in the cells. The GCF2 transfectants also showed reduced accumulation of cisplatin and increased resistance. siRNA targeted to GCF2 suppressed the expression of GCF2 in cisplatin-resistant cells, reactivated RhoA expression, and restored the fine structure of actin microfilaments. MRP1 was also relocated to the cell surface. siRNA targeted to RhoA increased resistance 3-fold in KB-3-1 and KB-CP.5 cells. These data for the first time demonstrate a novel complex regulatory pathway downstream from GCF2 involving the small GTPase RhoA, actin/filamin dynamics, and membrane protein traffickin...Continue Reading

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Citations

Oct 31, 2015·Annual Review of Pharmacology and Toxicology·Michael M GottesmanJean-Pierre Gillet
Apr 29, 2015·Breast Cancer Research and Treatment·Ji WenXiaodong Cai
Mar 30, 2013·International Journal of Molecular Sciences·Xiaojuan ChiJi-Long Chen
Aug 7, 2013·Molecular and Cellular Biology·Byung-Kwan BanJin-A Lee
Aug 21, 2020·Calcified Tissue International·Virginia M StiffelKin-Hing William Lau
Jun 21, 2020·Cancers·Nguyen Minh Tuan, Chang Hoon Lee
Dec 14, 2013·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yinghua LiTianfeng Chen
Jan 26, 2020·Cancer Letters·Chun-Wen ZhengEn-Min Li
Mar 13, 2021·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Shuhei KawasakiMichiaki Unno

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