Human mitochondrial Mrs2 protein promotes multidrug resistance in gastric cancer cells by regulating p27, cyclin D1 expression and cytochrome C release.
Human mitochondrial Mrs2 protein (hsaMrs2p) is a magnesium transporter in mitochondria inner membrane. It was identified as an upregulated gene in a multidrug-resistant (MDR) gastric cancer cell line compared to its parental cells by subtractive hybridization. To further explore the role of hsaMrs2p in MDR of gastric cancer cells, the cDNA encoding hsaMrs2p was generated and mouse antisera against hsaMrs2p was raised with recombinant hsaMrs2p as the immunogen. HsaMrs2p expression could positively regulate adriamycin resistance of SGC7901/ADR cells both in vitro and in vivo. Further study showed that hsaMrs2p increased adriamycin-releasing index. Its upregulation inhibited adriamycin-induced apoptosis, probably by suppressing Bax induced cytochrome C release from mitochondria. Additionally, hsaMrs2p promoted cell growth and cells with decreased hsaMrs2p exhibited significant inhibition of cell growth with G(1) cell cycle arrest. By enhanced hsaMrs2p expression, p27 was downregulated whereas cyclinD1 was upregulated. Our results provide new insights into the function of hsaMrs2p that may be a promising target for MDR reversal therapy.
Chen
Yu
Y
State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi Province, China.
Wei
Xufeng
X
Yan
Pengfei
P
Han
Ying
Y
Sun
Shiren
S
Wu
Kaichun
K
Fan
Daiming
D
D000818:Animals; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis* / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D027682:Cation Transport Proteins; C430096:MRS2 protein, human; D024101:Mitochondrial Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; D045304:Cytochromes c