Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes.
Using transcripts initiated at a chromosomally integrated retrovirus-based promoter to perturb gene expression randomly in human prostate cancer cells, we isolated cell clones resistant to taxane lethality and discovered the role of a previously uncharacterized gene, txr1, in this phenotype. We show that txr1 impedes taxane-induced apoptosis in tumor cells by transcriptionally down-regulating the production of thrombospondin-1 (TSP-1)--known earlier for both its anti-angiogenic and proapoptotic actions. Decrease of Txr1 or treatment with TSP-1 or TSP-1 mimetic peptide sensitized cells to taxane cytotoxicity by activating signaling through the CD47 receptor (also known as the integrin-associated protein), whereas interference with CD47 function reduced taxane-induced cell death. Cellular abundance of Txr1 and TSP-1 varied inversely, and alteration of the level of both proteins correlated highly with taxol resistance in 13 of 19 NCI-60 cancer cell lines. Our results reveal a hitherto unsuspected mechanism of taxane resistance, elucidate the role of txr1 in this resistance, and identify txr1 as a regulator of TSP-1 production and an agent for its chemotherapeutic modulation.
Lih
Chih-Jian
CJ
Department of Genetics, Stanford University School of Medicine, Stanford University, California 94305, USA.
Wei
Wensheng
W
Cohen
Stanley N
SN
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012097:Repressor Proteins / Q000502:physiology*; D043823:Taxoids / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; C513606:PRR13 protein, human; D012097:Repressor Proteins; D043823:Taxoids; D019700:Thrombospondin 1; C080625:taxane