RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis.
Cancer cells are more susceptible to chemotherapeutic agent-induced apoptosis than their normal counterparts. Although it has been demonstrated that the increased sensitivity results from deregulation of oncoproteins during cancer development (Evan, G. I., and Vousden, K. H. (2001) Nature 411, 342-348; Green, D. R., and Evan, G. I. (2002) Cancer Cell 1, 19-30), little is known about the signaling pathways leading to changes in the apoptotic threshold in cancer cells. Here we show that low RKIP expression levels in tumorigenic human prostate and breast cancer cells are rapidly induced upon chemotherapeutic drug treatment, sensitizing the cells to apoptosis. We show that the maximal RKIP expression correlates perfectly with the onset of apoptosis. In cancer cells resistant to DNA-damaging agents, treatment with the drugs does not up-regulate RKIP expression. However, ectopic expression of RKIP resensitizes DNA-damaging agent-resistant cells to undergo apoptosis. This sensitization can be reversed by up-regulation of survival pathways. Down-regulation of endogenous RKIP by expression of antisense and small interfering RNA (siRNA) confers resistance on sensitive cancer cells to anticancer drug-induced apoptosis. Our studies suggest that RKIP may represent a novel effector of signal transduction pathways leading to apoptosis and a prognostic marker of the pathogenesis of human cancer cells and tumors after treatment with clinically relevant chemotherapeutic drugs.
Chatterjee
Devasis
D
Department of Medicine, Brown University and Rhode Island Hospital, Providence, Rhode Island 02903, USA.
Bai
Yin
Y
Wang
Zhe
Z
Beach
Sandy
S
Mott
Stephanie
S
Roy
Rajat
R
Braastad
Corey
C
Sun
Yaping
Y
Mukhopadhyay
Asok
A
Aggarwal
Bharat B
BB
Darnowski
James
J
Pantazis
Panayotis
P
Wyche
James
J
Fu
Zheng
Z
Kitagwa
Yasuhide
Y
Keller
Evan T
ET
Sedivy
John M
JM
Yeung
Kam C
KC
D000727:Androgen-Binding Protein / Q000502:physiology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D015536:Down-Regulation; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D049488:Phosphatidylethanolamine Binding Protein; D010957:Plasmids / Q000378:metabolism; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000473:pathology*; D016372:RNA, Antisense / Q000737:chemistry; D034741:RNA, Small Interfering / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D000727:Androgen-Binding Protein; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D016372:RNA, Antisense; D034741:RNA, Small Interfering; D004247:DNA