Skip to main content

Advertisement

SpringerLink
Log in

RNA interference-directed caveolin-1 knockdown sensitizes SN12CPM6 cells to doxorubicin-induced apoptosis and reduces lung metastasis

  • Research Article
  • Published:
Tumor Biology

Abstract

Human renal cell carcinoma (HRCC) is characterized by a high level of resistance to all treatment modalities. Therefore, the investigation of global gene expression in HRCC might help understand its biologic behavior and develop treatment strategies. Using cDNA microarray analysis, we initially compared gene expression profiles between HRCCs and adjacent normal tissues, and found that 87 were up-regulated and 127 genes were down-regulated. Next, a subset of genes, twofold differentially expressed, were validated by Northern blotting. Unexpectedly, caveolin-1, a gene reported to be a tumor suppressor gene, was found to be up-regulated in HRCC tissues. Expression level of caveolin-1 in SN12CPM6 (high metastatic clone) was higher than in SN12C (low metastatic clone), and SN12CPM6 was more resistant to doxorubicin (DXR) than SN12C. Caveolin-1 gene was slightly induced in surviving SN12C cells after DXR treatment. Furthermore, SN12CPM6-siCav1 cells, which were transfected with siRNA of cavelon-1 gene, were more sensitive to DXR, compared to SN12CPM6, but reduction of caveolin-1 gene expression did not affect tumor formation in subcapsule of kidney and lung metastasis. On the other hand, induction of caveolin-1 gene affected the production of lung metastasis under anti-cancer drug treatment: the incidence of pulmonary metastasis was significantly lower in SCID mice injected with SN12CPM6-siCav1 cells, and the number of pulmonary nodules decreased significantly (p = 0.0004). The above results together suggest that caveolin-1 may confer a growth advantage to cancer cells during DXR chemotherapy and surviving HRCC cells eventually might develop lung metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mickisch GH. Chemoresistance of renal cell carcinoma: 1986-1994. World J Urol. 1994;12:214–23.

    CAS  PubMed  Google Scholar 

  2. Yu DS, Ma CP, Chang SY. Establishment and characterization of renal cell carcinoma cell lines with multidrug resistance. Urol Res. 2000;28:86–92.

    Article  CAS  PubMed  Google Scholar 

  3. Tan MH, Rogers CG, Cooper JT, Ditlev JA, Maatman TJ, Yang X, et al. Gene expression profiling of renal cell carcinoma. Clin Cancer Res. 2004;10:6315S–21S.

    Article  CAS  PubMed  Google Scholar 

  4. Yang XJ, Sugimura J, Schafernak KT, Tretiakova MS, Han M, Vogelzang NJ, et al. Classification of renal neoplasms based on molecular signatures. J Urol. 2006;175:2302–6.

    Article  CAS  PubMed  Google Scholar 

  5. Parton RG. Caveolae and caveolins. Curr Opin Cell Biol. 1996;8:542–8.

    Article  CAS  PubMed  Google Scholar 

  6. Bouras T, Lisanti MP, Pestell RG. Caveolin-1 in breast cancer. Cancer Biol Ther. 2004;3:931–41.

    Article  CAS  PubMed  Google Scholar 

  7. Hino M, Doihara H, Kobayashi K, Aoe M, Shimizu N. Caveolin-1 as tumor suppressor gene in breast cancer. Surg Today. 2003;33:486–90.

    CAS  PubMed  Google Scholar 

  8. Li L, Yang G, Ebara S, Satoh T, Nasu Y, Timme TL, et al. Caveolin-1 mediates testosterone-stimulated survival/clonal growth and promotes metastatic activities in prostate cancer cells. Cancer Res. 2001;61:4386–92.

    CAS  PubMed  Google Scholar 

  9. Ho CC, Huang PH, Huang HY, Chen YH, Yang PC, Hsu SM. Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. Am J Pathol. 2002;161:1647–56.

    CAS  PubMed  Google Scholar 

  10. Sagara Y, Mimori K, Yoshinaga K, Tanaka F, Nishida K, Ohno S, et al. Clinical significance of caveolin-1, caveolin-2 and her2/neu mrna expression in human breast cancer. Br J Cancer. 2004;91:959–65.

    CAS  PubMed  Google Scholar 

  11. Belanger MM, Gaudreau M, Roussel E, Couet J. Role of caveolin-1 in etoposide resistance development in A549 lung cancer cells. Cancer Biol Ther. 2004;3:954–9.

    Article  CAS  PubMed  Google Scholar 

  12. Ho CC, Kuo SH, Huang PH, Huang HY, Yang CH, Yang PC. Caveolin-1 expression is significantly associated with drug resistance and poor prognosis in advanced non-small cell lung cancer patients treated with gemcitabine-based chemotherapy. Lung Cancer. 2008;59:105–10.

    Article  PubMed  Google Scholar 

  13. Lavie Y, Fiucci G, Liscovitch M. Up-regulation of caveolae and caveolar constituents in multidrug-resistant cancer cells. J Biol Chem. 1998;273:32380–3.

    Article  CAS  PubMed  Google Scholar 

  14. Belanger MM, Roussel E, Couet J. Up-regulation of caveolin expression by cytotoxic agents in drug-sensitive cancer cells. Anticancer Drugs. 2003;14:281–7.

    Article  CAS  PubMed  Google Scholar 

  15. Mulders P, Figlin R, de Kernion JB, Wiltrout R, Linehan M, Parkinson D, et al. Renal cell carcinoma: recent progress and future directions. Cancer Res. 1997;57:5189–95.

    CAS  PubMed  Google Scholar 

  16. Mickisch GH, Roehrich K, Koessig J, Forster S, Tschada RK, Alken PM. Mechanisms and modulation of multidrug resistance in primary human renal cell carcinoma. J Urol. 1990;144:755–9.

    CAS  PubMed  Google Scholar 

  17. Fukuda N, Tahira Y, Matsuda H, Matsumoto K. Transforming growth factor-beta as a treatment target in renal diseases. J Nephrol. 2009;22:708–15.

    CAS  PubMed  Google Scholar 

  18. Kominsky SL, Doucet M, Brady K, Weber KL. Tgf-beta promotes the establishment of renal cell carcinoma bone metastasis. J Bone Miner Res. 2007;22:37–44.

    Article  CAS  PubMed  Google Scholar 

  19. Thorburn E, Kolesar L, Brabcova E, Petrickova K, Petricek M, Jaresova M, et al. Cxc and cc chemokines induced in human renal epithelial cells by inflammatory cytokines. APMIS. 2009;117:477–87.

    Article  CAS  PubMed  Google Scholar 

  20. Bedke J, Nelson PJ, Kiss E, Muenchmeier N, Rek A, Behnes CL, et al. A novel cxcl8 protein-based antagonist in acute experimental renal allograft damage. Mol Immunol. 2010;47:1047–57.

    Article  CAS  PubMed  Google Scholar 

  21. Lee SW, Reimer CL, Oh P, Campbell DB, Schnitzer JE. Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene. 1998;16:1391–7.

    Article  CAS  PubMed  Google Scholar 

  22. Shridhar V, Sun QC, Miller OJ, Kalemkerian GP, Petros J, Smith DI. Loss of heterozygosity on the long arm of human chromosome 7 in sporadic renal cell carcinomas. Oncogene. 1997;15:2727–33.

    Article  CAS  PubMed  Google Scholar 

  23. Yang G, Truong LD, Timme TL, Ren C, Wheeler TM, Park SH, et al. Elevated expression of caveolin is associated with prostate and breast cancer. Clin Cancer Res. 1998;4:1873–80.

    CAS  PubMed  Google Scholar 

  24. Williams TM, Hassan GS, Li J, Cohen AW, Medina F, Frank PG, et al. Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of cav-1 delays advanced prostate tumor development in tramp mice. J Biol Chem. 2005;280:25134–45.

    Article  CAS  PubMed  Google Scholar 

  25. Campbell L, Gumbleton M, Griffiths DF. Caveolin-1 overexpression predicts poor disease-free survival of patients with clinically confined renal cell carcinoma. Br J Cancer. 2003;89:1909–13.

    Article  CAS  PubMed  Google Scholar 

  26. Joo HJ, Oh DK, Kim YS, Lee KB, Kim SJ. Increased expression of caveolin-1 and microvessel density correlates with metastasis and poor prognosis in clear cell renal cell carcinoma. BJU Int. 2004;93:291–6.

    Article  CAS  PubMed  Google Scholar 

  27. Park WY, Park JS, Cho KA, Kim DI, Ko YG, Seo JS, et al. Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells. J Biol Chem. 2000;275:20847–52.

    Article  CAS  PubMed  Google Scholar 

  28. Cho KA, Ryu SJ, Oh YS, Park JH, Lee JW, Kim HP, et al. Morphological adjustment of senescent cells by modulating caveolin-1 status. J Biol Chem. 2004;279:42270–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This research was supported by a grant of Medical Research Center for Environmental Toxicogenomics and Proteomics (R13-2003-010-02005-0) funded by Korea Science and Engineering Foundations and Ministry of Science & Technology.

Author information

Authors and Affiliations

  1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    Juwon Park, Chansu Lee & Sung-Soo Yoon

  2. Department of Biomedical Science, Hanyang University College of Medicine, Seoul, Republic of Korea

    Eunkyung Bae

  3. Department of Pathology, College of Medicine, Korea University, Anam-dong 5 ga, Sungbuk-gu, Seoul, Republic of Korea

    Yang Seok Chae, Kwang-Sung Ahn & Nam Hee Won

  4. Environmental Toxicogenomic and Proteomics Research Center, Korea University, Seoul, Republic of Korea

    Kwang-Sung Ahn & Nam Hee Won

Authors
  1. Juwon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eunkyung Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chansu Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sung-Soo Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yang Seok Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kwang-Sung Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nam Hee Won
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kwang-Sung Ahn or Nam Hee Won.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, J., Bae, E., Lee, C. et al. RNA interference-directed caveolin-1 knockdown sensitizes SN12CPM6 cells to doxorubicin-induced apoptosis and reduces lung metastasis. Tumor Biol. 31, 643–650 (2010). https://doi.org/10.1007/s13277-010-0081-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-010-0081-1

Keywords

Search

Navigation