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The CLN3 gene is a novel molecular target for cancer drug discovery.

Publication ,  Journal Article
Rylova, SN; Amalfitano, A; Persaud-Sawin, D-A; Guo, W-X; Chang, J; Jansen, PJ; Proia, AD; Boustany, R-M
Published in: Cancer Res
February 1, 2002

Juvenile Batten disease is a neurodegenerative disease caused by accelerated apoptotic death of photoreceptors and neurons attributable to defects in the CLN3 gene. CLN3 is antiapoptotic when overexpressed in NT2 neuronal precursor cells. CLN3 negatively modulates endogenous ceramide levels in NT2 cells and acts upstream of ceramide generation. Because defects in regulation of apoptosis are involved in the development of cancer, we evaluated the expression of CLN3 on both mRNA and protein levels in a variety of cancer cell lines and solid colon cancer tissue. We also observed the effect of the blocking of CLN3 protein expression on cancer cell growth, survival, ceramide production, and apoptosis by using an adenovirus-bearing antisense CLN3 construct. We show that CLN3 mRNA and protein are overexpressed in glioblastoma (U-373G and T98g), neuroblastoma (IMR-32 and SK-N-MC), prostate (Du145, PC-3, and LNCaP), ovarian (SK-OV-3, SW626, and PA-1), breast (BT-20, BT-549, and BT-474), and colon (SW1116, SW480, and HCT 116) cancer cell lines but not in pancreatic (CAPAN and As-PC-1) or lung (A-549 and NCI-H520) cancer cell lines. CLN3 is also up-regulated in mouse melanoma and breast carcinoma cancer cell lines. We found CLN3 expression is 22-330% higher than in corresponding normal colon control tissue in 8 of 10 solid colon tumors. An adenovirus-expressing antisense CLN3 (Ad-AS-CLN3) blocks CLN3 protein expression in DU-145, BT-20, SW1116, and T98g cancer cell lines as seen by Western blot. Blocking of CLN3 expression using Ad-AS-CLN3 inhibits growth and viability of cancer cells. It also causes elevation in endogenous ceramide production through de novo ceramide synthesis and results in increased apoptosis as shown by propidium iodide and JC-1 staining. This suggests that Ad-AS-CLN3 may be an option for therapy in some cancers. More importantly these results suggest that CLN3 is a novel molecular target for cancer drug discovery.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

February 1, 2002

Volume

62

Issue

3

Start / End Page

801 / 808

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Thymidine
  • Sphingomyelins
  • RNA, Messenger
  • Proteins
  • Protein Biosynthesis
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Neuronal Ceroid-Lipofuscinoses
 

Citation

APA
Chicago
ICMJE
MLA
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Rylova, S. N., Amalfitano, A., Persaud-Sawin, D.-A., Guo, W.-X., Chang, J., Jansen, P. J., … Boustany, R.-M. (2002). The CLN3 gene is a novel molecular target for cancer drug discovery. Cancer Res, 62(3), 801–808.
Rylova, Svetlana N., Andrea Amalfitano, Dixie-Ann Persaud-Sawin, Wei-Xing Guo, Jerry Chang, Paul J. Jansen, Alan D. Proia, and Rose-Mary Boustany. “The CLN3 gene is a novel molecular target for cancer drug discovery.Cancer Res 62, no. 3 (February 1, 2002): 801–8.
Rylova SN, Amalfitano A, Persaud-Sawin D-A, Guo W-X, Chang J, Jansen PJ, et al. The CLN3 gene is a novel molecular target for cancer drug discovery. Cancer Res. 2002 Feb 1;62(3):801–8.
Rylova, Svetlana N., et al. “The CLN3 gene is a novel molecular target for cancer drug discovery.Cancer Res, vol. 62, no. 3, Feb. 2002, pp. 801–08.
Rylova SN, Amalfitano A, Persaud-Sawin D-A, Guo W-X, Chang J, Jansen PJ, Proia AD, Boustany R-M. The CLN3 gene is a novel molecular target for cancer drug discovery. Cancer Res. 2002 Feb 1;62(3):801–808.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

February 1, 2002

Volume

62

Issue

3

Start / End Page

801 / 808

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Thymidine
  • Sphingomyelins
  • RNA, Messenger
  • Proteins
  • Protein Biosynthesis
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Neuronal Ceroid-Lipofuscinoses