Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model.
Protein serine/threonine kinase CK2 (formerly casein kinase 2) is a ubiquitous protein kinase that plays key roles in cell growth, proliferation, and survival. We have shown previously that its molecular down-regulation induces apoptosis in cancer cells in culture. Here, we have employed a xenograft model of prostate cancer to extend these studies to determine whether antisense CK2alpha evokes a similar response in vivo. A single dose of antisense CK2alpha oligodeoxynucleotide given directly into the PC3-LN4 xenograft tumor in nude mouse induced a dose- and time-dependent tumor cell death in vivo. The tumor was completely resolved at the higher tested dose of the antisense. Cell death was due to apoptosis and correlated with a potent down-regulation of the CK2alpha message and loss of CK2 from the nuclear matrix in the xenograft tissue as well as in cancer cells in culture. These observations accorded with several of the earlier studies indicating that loss of CK2 from the nuclear matrix is associated with induction of apoptosis. Comparison of the effects of antisense CK2alpha oligodeoxynucleotide on cancer versus normal or noncancer cells showed that the concentration of antisense CK2alpha that elicited extensive apoptosis in tumor cells in culture or xenograft tumors in vivo had a relatively small or minimal effect on noncancer cells in culture or on normal prostate gland subjected to orthotopic injection of antisense oligodeoxynucleotide in vivo. The basis for the difference in sensitivity of cancer versus noncancer cells to antisense CK2alpha is unknown at this time; however, this differential response under similar conditions of treatment may be significant in considering the potential feasibility of targeting the CK2 signal for induction of apoptosis in cancer cells in vivo. Although much further work will be needed to establish the feasibility of targeting CK2 for cancer therapy, to our knowledge, this is the first report to provide important new evidence as an initial "proof of principle" for the potential application of antisense CK2alpha in cancer therapy, paving the way for future detailed studies of approaches to targeting CK2 in vivo to induce cancer cell death.
Slaton
Joel W
JW
Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota, USA.
Unger
Gretchen M
GM
Sloper
Daniel T
DT
Davis
Alan T
AT
Ahmed
Khalil
K
D000818:Animals; D017209:Apoptosis; D047390:Casein Kinase II / Q000235:genetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D047390:Casein Kinase II