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Updated: May 31, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Systemic administration of antisense oligonucleotides simultaneously targeting CK2α and α' subunits reduces
Janeen H Trembley1, Gretchen M Unger, Diane K Tobolt
1Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN 55417, USA.
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.
Insights
This study developed a bispecific antisense oligonucleotide targeting both CK2α and CK2α' catalytic subunits. This novel therapy effectively reduced prostate tumor size and induced cancer cell death with minimal toxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Casein kinase 2 (CK2) is a protein kinase that promotes cell proliferation and suppresses apoptosis.
- Elevated CK2 expression is a hallmark of various cancers.
- Previous studies showed antisense oligonucleotides targeting CK2α reduced prostate tumor size.
Purpose of the Study:
- To design and evaluate a bispecific antisense oligonucleotide (bs-AS-CK2) targeting both CK2α and CK2α' catalytic subunits.
- To assess the efficacy of bs-AS-CK2 in reducing tumor growth and inducing apoptosis in prostate cancer models.
- To investigate the safety and biodistribution of bs-AS-CK2.
Main Methods:
- Development of a bispecific antisense phosphorothioate oligonucleotide (PTO) targeting both CK2α and CK2α'.
- In vitro studies on cultured cancer cells to assess protein expression, proliferation, and apoptosis.
- In vivo studies using orthotopic prostate xenograft models in mice, including biodistribution, toxicity, and efficacy assessments.
- Analysis of downstream signaling pathway proteins (NF-κB p65 and AKT).
Main Results:
- bs-AS-CK2 effectively reduced both CK2α and CK2α' protein expression in cultured cells.
- bs-AS-CK2 demonstrated potent anti-proliferative and pro-apoptotic effects in vitro.
- In vivo administration of bs-AS-CK2 led to significant reduction in orthotopic prostate tumor size.
- Low doses of bs-AS-CK2, administered over multiple days, were effective and showed no damage to normal tissues.
- Downregulation of key signaling proteins NF-κB p65 and AKT was observed in tumors.
Conclusions:
- Bispecific targeting of CK2α and CK2α' catalytic subunits with bs-AS-CK2 is a promising therapeutic strategy for prostate cancer.
- This approach effectively reduces tumor burden and induces cancer cell death.
- bs-AS-CK2 exhibits a favorable safety profile and therapeutic potential for cancer elimination.
