Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Suppresion of Ras Oncogenic Activity by Farnesyl Transferase Inhibitors, YH3938 and YH3945

Farnesyl transferase 억제제인 YH3938 및 YH3945에 의한 Ras 발암원성 억제

  • Oh, Myung-Ju (Department of Nanomedical Engineering, Pusan National University) ;
  • Kim, Nong-Yeon (Department of Nanomedical Engineering, Pusan National University) ;
  • Lim, Su-Eun (Department of Nanomedical Engineering, Pusan National University) ;
  • Chung, Young-Hwa (Department of Nanomedical Engineering, Pusan National University) ;
  • Jhun, Byung-H. (Department of Nanomedical Engineering, Pusan National University)
  • 오명주 (부산대학교 나노메디컬공학과) ;
  • 김농연 (부산대학교 나노메디컬공학과) ;
  • 임수은 (부산대학교 나노메디컬공학과) ;
  • 정영화 (부산대학교 나노메디컬공학과) ;
  • 전병학 (부산대학교 나노메디컬공학과)
  • Received : 2009.11.11
  • Accepted : 2009.12.03
  • Published : 2010.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

Ras genes are responsible for up to 30% of human tumor mutations and are composed of three isoforms: H-Ras, K-Ras and N-Ras. The post-translational modification of the CAAX motif of the Ras protein is essential in Ras actions. In the present study, we studied the effects of novel farnesyl transferase inhibitors (FTIs), YH3938 and YH3945, on the actions of oncogenic mutants of H-Ras, K-Ras and N-Ras. YH3938 and YH3945 completely reverted the proliferation and morphology of oncogenic H-Ras-transformed Rat2 cells, but not of oncogenic K-Ras-transformed Rat2 cells. Oncogenic N-Ras-transformed Rat2 cells were slightly affected. Activation of SRE promoters by oncogenic H-Ras and N-Ras, but not by K-Ras, were inhibited by treatment with YH3938 and YH3945. Using bandshift analysis, YH3938 suppressed the processing of oncogenic H-Ras and N-Ras, but not that of oncogenic K-Ras protein. YH3945 only inhibited the processing of H-Ras. From these results, we conclude that YH3938 and YH3945 specifically inhibit actions of oncogenic H-Ras through inhibition of its farnesylation, that YH3938 also inhibits N-Ras activity in a dose-dependent manner, and that these drugs have no effect on oncogenic K-Ras activity.

Ras 유전자는 30%의 인간암에서 변이가 발견되며 세 종류의 isoform, H-Ras, K-Ras 및 N-Ras로 구성되어 있다. Ras 단백질의 CAAX motif에 farnesylation과 같은 번역 후 변형은 Ras의 활성에 필수 요소이다. 본 연구에서는 새로운 farnesyl transferase 억제제인 YH3938과 YH3945의 발암원성 H-Ras, K-Ras 및 N-Ras의 작용에 대한 영향을 조사하였다. YH3938과 YH3945는 발암원성 H-Ras에 의해 형질전환된 Rat2 세포의 증식과 형태 변화를 억제하였으나 K-Ras에 대해서는 효과가 없었다. N-Ras에 대해서는 약한 영향이 있었다. H-Ras와 N-Ras에 의한 SRE promoter 활성화는 YH3938과 YH3945에 의해 억제되었으나, K-Ras에는 영향이 없었다. Ras 단백질의 bandshift 분석을 통해 YH3938은 H-Ras와 N-Ras의 번역 후 변환을 억제하였으나, K-Ras에는 영향이 없었다. YH3945는 H-Ras의 변환에만 영향이 있었다. 결론적으로 YH3938과 YH3945는 H-Ras의 farnesylation을 억제하여 그 발암원성을 억제하며, YH3938은 N-Ras 작용을 농도의존적으로 억제하며, K-ras에 대해서는 영향이 없음을 알 수 있었다.

Keywords

References

  1. Adjei, A. A., C. Erlichman, J. N. Davis, D. L. Cutler, J. A. Sloan, R. S. Marks, L. J. Hanson, P. A. Svingen, P. Atherton, W. R. Bishop, P. Kirschmeier, and S. H. Kaufmann. 2000. A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res. 60, 1871-1877.
  2. Agrawal, A. G. and R. R. Somani. 2009. Farnesyltransferase inhibitor as anticancer agent. Mini Rev. Med. Chem. 9, 638-652. https://doi.org/10.2174/138955709788452702
  3. Ashar, H. R., L. James, K. Gray, D. Carr, M. McGuirk, E. Maxwell, S. Black, L. Armstrong, R. J. Doll, A. G. Taveras, W. R. Bishop, and P. Kirschmeier. 2001. The farnesyl transferase inhibitor SCH 66336 induces a G(2)--> M or G(1) pause in sensitive human tumor cell lines. Exp. Cell Res. 262, 17-27. https://doi.org/10.1006/excr.2000.5076
  4. Ashby, M. N. 1998. CaaX converting enzymes. Curr. Opin. Lipidol. 9, 99-102. https://doi.org/10.1097/00041433-199804000-00004
  5. Barbacid, M. 1987. Ras genes. Annu. Rev. Biochem. 56, 779-827. https://doi.org/10.1146/annurev.bi.56.070187.004023
  6. Basso, A. D., A. Mirza, G. Liu, B. J. Long, W. R. Bishop, and P. Kirschmeier. 2005. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J. Biol. Chem. 280, 31101-31108. https://doi.org/10.1074/jbc.M503763200
  7. Basso, A. D., P. Kirschmeier, and W. R. Bishop. 2006. Lipid posttranslational modifications. Farnesyl transferase inhibitors. J. Lipid Res. 47, 15-31. https://doi.org/10.1194/jlr.R500012-JLR200
  8. Bos, J. L. 1989. Ras oncogenes in human cancer: a review. Cancer Res. 49, 4682-4689.
  9. Bourne, H. R., D. A. Sanders, and F. McCormick. 1990. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348, 125-132. https://doi.org/10.1038/348125a0
  10. Chiu, V. K., T. Bivona, A. Hach, J. B. Sajous, J. Silletti, H. Wiener, R. L. 2nd. Johnson, A. D. Cox, and M. R. Philips. 2002. RAS signalling on the endoplasmic reticulum and the Golgi. Nat. Cell Biol. 4, 343-350.
  11. Gibbs, J. B., A. Oliff, and N. E. Kohl. 1994. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77, 175-178. https://doi.org/10.1016/0092-8674(94)90308-5
  12. Glomset, J. A. and C. C. Farnsworth. 1994. Role of protein modification reactions in programming interactions between RAS-related GTPases and cell membranes. Annu. Rev. Cell Biol. 10, 181-205. https://doi.org/10.1146/annurev.cb.10.110194.001145
  13. Han, J. Y., S. H. Oh, F. Morgillo, J. N. Myers, E. Kim, W. K. Hong, and H. Y. Lee. 2005. Hypoxia-inducible factor 1a and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. J. Natl. Cancer Inst. 97, 1272-1286. https://doi.org/10.1093/jnci/dji251
  14. Hanrahan, E. O., M. S. Kies, B. S. Glisson, F. R. Khuri, L. Feng, H. T. Tran, L. E. Ginsberg, M. T. Truong, W. K. Hong, and E. S. Kim. 2009. A phase II study of Lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck. Am. J. Clin. Oncol. 32, 274-279. https://doi.org/10.1097/COC.0b013e318187dd57
  15. Lantry, L. E., Z. Zhang, R. Yao, K. A. Crist, Y. Wang, J. Ohkanda, A. D. Hamilton, S. M. Sebti, R. A. Lubet, and M. You. 2000. Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 21, 113-116. https://doi.org/10.1093/carcin/21.1.113
  16. Lowy, D. R. and B. M. Willumsen. 1993. Function and regulation of ras. Annu Rev. Biochem. 62, 851-891. https://doi.org/10.1146/annurev.bi.62.070193.004223
  17. Malumbres, M. and M. Barbacid. 2003. RAS oncogenes: the first 30 years. Nat. Rev. Cancer 3, 459-465. https://doi.org/10.1038/nrc1097
  18. Mayo, M. W., C. Y. Wang, P. C. Cogswell, K. S. Rogers-Graham, S. W. Lowe, C. J. Der, and A. S. Jr. Baldwin. 1997. Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278, 1812-1815. https://doi.org/10.1126/science.278.5344.1812
  19. Nagasu, T., K. Yoshimatsu, C. Rowell, M. D. Lewis, and A. M. Garcia. 1995. Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res. 55, 5310-5314.
  20. O'Regan, R. M. and F. R. Khuri. 2004. Farnesyl transferase inhibitors: the next targeted therapies for breast cancer? Endocr. Relat. Cancer 11, 191-205. https://doi.org/10.1677/erc.0.0110191
  21. Oh, S. H., W. Y. Kim, J. H. Kim, M. N. Younes, A. K. El-Naggar, J. N. Myers, M. Kies, P. Cohen, F. Khuri, W. K. Hong, and H. Y. Lee. 2006. Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma. Clin. Cancer Res. 12, 653-661. https://doi.org/10.1158/1078-0432.CCR-05-1725
  22. Satoh, T., M. Nakafuku, and Y. Kaziro. 1992. Function of Ras as a molecular switch in signal transduction. J. Biol. Chem. 267, 24149-24152.
  23. Whyte, D. B., P. Kirschmeier, T. N. Hockenberry, I. Nunez-Oliva, L. James, J. J. Catino, W. R. Bishop, and J. K. Pai. 1997. K-and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459-14464. https://doi.org/10.1074/jbc.272.22.14459
  24. Winter-Vann, A. M. and P. J. Casey. 2005. Post-prenylation-processing enzymes as new targets in oncogenesis. Nature Rev. Cancer 5, 405-412. https://doi.org/10.1038/nrc1612