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Systemic administration of antisense oligonucleotides simultaneously targeting CK2α and α′ subunits reduces orthotopic xenograft prostate tumors in mice

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Abstract

CK2 is a highly conserved, ubiquitous, signal responsive protein serine/threonine kinase. CK2 promotes cell proliferation and suppresses apoptosis, and increased CK2 expression is observed in all cancers examined. We previously reported that direct injection of antisense (AS) CK2α phosphorothioate oligonucleotides (PTO) into xenograft prostate tumors in mice significantly reduced tumor size. Downregulation of CK2α in tumor cells in vivo appeared to result in overexpression of CK2α′ protein. This suggested that in cancer cells downregulation of CK2α might be compensated by CK2α′ in vivo, prompting us to design a bispecific (bs) AS PTO (bs-AS-CK2) targeting both catalytic subunits. bs-AS-CK2 reduced CK2α and α′ protein expression, decreased cell proliferation, and induced apoptosis in cultured cells. Biodistribution studies of administered bs-AS-CK2 oligonucleotide demonstrated its presence in orthotopic prostate xenograft tumors. High dose injections of bs-AS-CK2 resulted in no damage to normal liver or prostate, but induced extensive cell death in tumor tissue. Intraperitoneal treatment with bs-AS-CK2 PTO decreased orthotopic tumor size and downregulated both CK2 mRNA and protein expression. Tumor reduction was accomplished using remarkably low doses and was improved by dividing the dose using a multi-day schedule. Decreased expression of the key signaling pathway proteins NF-κB p65 and AKT was also observed. We propose that the molecular downregulation of CK2 through bispecific targeting of the two catalytic subunits may be uniquely useful for therapeutic elimination of tumors.

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Abbreviations

AS:

Antisense

bs:

Bispecific

CK2:

Official acronym for former casein kinase 2 or II

CRPC:

Castration-resistant prostate cancer

d:

Day(s)

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

H&E:

Hematoxylin and eosin stain

h:

Hour(s)

HNSCC:

Head and neck squamous cell carcinoma

i.p.:

Intraperitoneal

i.v.:

Intravenous

kDa:

Kilo Dalton

LDH:

Lactate dehydrogenase

min:

Minutes

NF-κB:

Nuclear factor kappa B

OGN:

Oligonucleotide

PBS:

Phosphate-buffered saline

PCa:

Prostate cancer

PCR:

Polymerase chain reaction

PKB:

Protein kinase B

PTO:

Phosphorothioate-modified oligodeoxynucleotide

RFP:

Red fluorescent protein

s:

Seconds

Ser:

Serine

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Acknowledgments

The authors thank Ms. Lindsey M. Watch for excellent technical assistance. Grant Sponsors: Department of Veterans Affairs Medical Research Merit Review Funds (KA); National Cancer Institute grant numbers UO1-CA15062 (KA) and RO1-CA150182 (KA); National Institute of Health grant number R01-DK067436 (BK).

Conflict of interest

None.

Author information

Author notes

  1. Guixia Wang

    Present address: The First Hospital of Jilin University, Jilin, China

  2. Kashif A. Ahmad

    Present address: Northwestern Health Sciences University, Bloomington, MN, 55431, USA

Authors and Affiliations

  1. Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, 55417, USA

    Janeen H. Trembley, Guixia Wang, Kashif A. Ahmad, Betsy T. Kren & Khalil Ahmed

  2. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55417, USA

    Janeen H. Trembley, Guixia Wang, Kashif A. Ahmad & Khalil Ahmed

  3. Department of Urology, University of Minnesota, Minneapolis, MN, 55417, USA

    Joel W. Slaton & Khalil Ahmed

  4. Department of Medicine, University of Minnesota, Minneapolis, MN, 55417, USA

    Betsy T. Kren

  5. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55417, USA

    Khalil Ahmed

  6. GeneSegues Inc., Minneapolis, MN, 55417, USA

    Gretchen M. Unger, Diane K. Tobolt & Vicci L. Korman

  7. Cellular and Molecular Biochemistry Research Laboratory (151), Minneapolis VA Health Care System, University of Minnesota, One Veterans Drive, Minneapolis, MN, 55417, USA

    Khalil Ahmed

Authors
  1. Janeen H. Trembley
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  2. Gretchen M. Unger
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  3. Diane K. Tobolt
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  4. Vicci L. Korman
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  5. Guixia Wang
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  6. Kashif A. Ahmad
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  7. Joel W. Slaton
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  8. Betsy T. Kren
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  9. Khalil Ahmed
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Correspondence to Khalil Ahmed.

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Trembley, J.H., Unger, G.M., Tobolt, D.K. et al. Systemic administration of antisense oligonucleotides simultaneously targeting CK2α and α′ subunits reduces orthotopic xenograft prostate tumors in mice. Mol Cell Biochem 356, 21–35 (2011). https://doi.org/10.1007/s11010-011-0943-x

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  • DOI: https://doi.org/10.1007/s11010-011-0943-x

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