caa a22 4500 606175636 CHVBK 20210128100743.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00018-014-1831-9 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1831-9 PGRMC1 contributes to doxorubicin-induced chemoresistance in MES-SA uterine sarcoma [Elektronische Daten] [Szu-Ting Lin, Eugenie May, Jo-Fan Chang, Ren-Yu Hu, Lily Wang, Hong-Lin Chan] Chemotherapy is one of the major categories of medical oncology and a primary tumor treatment; however, the effectiveness of chemotherapy is restricted by drug resistance. Overcoming resistance to chemotherapy and investigating molecular targeted therapies are challenges currently faced during resistance management. Progesterone receptor membrane component 1 (PGRMC1) is an adapter protein mediating cholesterol synthesis, steroid signaling, and cytochrome p450 activation. Attention has recently focused on the role of PGRMC1 in cell survival, anti-apoptosis, and damage response. In the present study, we used knockdown and overexpression approaches in the following set of uterine sarcoma models to further evaluate the role of PGRMC1 in drug resistance: the doxorubicin-sensitive MES-SA cells and the doxorubicin-resistant MES-SA/DxR-2µM and MES-SA/DxR-8µM cells (with different levels of doxorubicin resistance). PGRMC1 repressed doxorubicin-induced cytotoxicity and exhibited an anti-apoptotic effect; it also promoted cell proliferation and cell cycle progression to the S phase. Of note, PGRMC1 overexpression led to the epithelial-mesenchymal transition (EMT) of the sensitive MES-SA cells, thus facilitating their migration and invasion. The combination of PGRMC1 knockdown and the P-glycoprotein inhibitor verapamil significantly decreased the viability of P-glycoprotein-overexpressing MES-SA/DxR-8μM cells after doxorubicin treatment. Taken together, our results show that PGRMC1 contributed to chemoresistance through cell proliferation, anti-apoptosis, and EMT induction, leading to the suggestion that PGRMC1 may serve as a therapeutic target in combination with an inhibitor in different drug resistance pathways and indicating the usefulness of predictive resistance biomarkers in uterine sarcoma. Springer Basel, 2015 Drug resistant nationallicence Andriamycin nationallicence Programed cell death nationallicence Uterine cancer nationallicence Metastasis nationallicence DAPI : 4′,6-Diamidino-2-phenylindole nationallicence DTT : Dithiothreitol nationallicence FBS : Fetal bovine serum nationallicence Insig : Insulin-induced gene nationallicence MTT : 3-(4,5-Dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide nationallicence PAIR-BP1 : Plasminogen activator inhibitor 1 mRNA-binding protein nationallicence PGRMC1 : Progesterone receptor membrane component 1 nationallicence Scap : SREBP cleavage activating protein nationallicence siRNA : Small interfering RNA nationallicence Lin Szu-Ting Institute of Bioinformatics and Structural Biology, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut May Eugenie Department of Life Science, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut Chang Jo-Fan Department of Life Science, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut Hu Ren-Yu Institute of Bioinformatics and Structural Biology, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut Wang Lily Institute of Molecular and Cellular Biology and Department of Medical Science, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsinchu, Taiwan aut Chan Hong-Lin Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut Cellular and Molecular Life Sciences Springer Basel 72/12(2015-06-01), 2395-2409 1420-682X 72:12<2395 2015 72 18 https://doi.org/10.1007/s00018-014-1831-9 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1831-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lin Szu-Ting Institute of Bioinformatics and Structural Biology, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut NATIONALLICENCE 700 1- May Eugenie Department of Life Science, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut NATIONALLICENCE 700 1- Chang Jo-Fan Department of Life Science, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut NATIONALLICENCE 700 1- Hu Ren-Yu Institute of Bioinformatics and Structural Biology, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut NATIONALLICENCE 700 1- Wang Lily Institute of Molecular and Cellular Biology and Department of Medical Science, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsinchu, Taiwan aut NATIONALLICENCE 700 1- Chan Hong-Lin Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, 30013, Hsin-chu, Taiwan aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/12(2015-06-01), 2395-2409 1420-682X 72:12<2395 2015 72 18