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Farnesyltransferase inhibitor (L-744,832) restores TGF-beta type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2.
Oncogene 2002; 21(51):7883-90O

Abstract

Activated ras is known to dysregulate TGF-beta signaling by altering the expression of TGF-beta type II receptor (RII). It is well documented that tumor cells harboring mutant ras are more resistant to radiation than cells with wild-type ras. In this study, we hypothesized that the use of farnesyltransferase inhibitor (FTI, L-744,832) may directly restore TGF-beta signaling through RII expression via ras dependent or independent pathway leading to induction of radiation sensitivity. Two pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2 were used in this study. FTI inhibited farnesylation of Ras protein more significantly in MIA PaCa-2 than BxPC-3 cells. In contrast, MIA PaCa-2 cells were resistant to radiation when compared to BxPC-3 cells. BxPC-3 cells were more resistant to FTI than MIA PaCa-2 cells. In combination treatment, no significant radiosensitizing effect of FTI was observed in BxPC-3 cells at 5 or 10 microM. However, in MIA PaCa-2 cells, a significant radiosensitizing effect was observed at both 5 and 10 microM concentrations (P>0.004). The TGF-beta effector gene p21(waf1/cip1) was elevated in combination treatment in MIA PaCa-2 but not in BxPC-3 cells. In MIA PaCa-2 cells, FTI induced TGF-beta responsive promoter activity as assessed by 3TP-luciferase activity. A further induction of luciferase activity was observed in MIA PaCa-2 cells treated with radiation and FTI. Induction of TGF-beta signaling by FTI was mediated through restoration of the RII expression, as demonstrated by RT-PCR analysis. In addition, re-expression of RII by FTI was associated with a decrease in DNA methyltransferase 1 (DNMT1) levels. Thus, these findings suggest that the L-744,832 treatment restores the RII expression through inhibition of DNMT1 levels causing induction of TGF-beta signaling by radiation and this forms a novel molecular mechanism of radiosensitization by FTI.

Authors+Show Affiliations

Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12420225

Citation

Alcock, Rachael A., et al. "Farnesyltransferase Inhibitor (L-744,832) Restores TGF-beta Type II Receptor Expression and Enhances Radiation Sensitivity in K-ras Mutant Pancreatic Cancer Cell Line MIA PaCa-2." Oncogene, vol. 21, no. 51, 2002, pp. 7883-90.
Alcock RA, Dey S, Chendil D, et al. Farnesyltransferase inhibitor (L-744,832) restores TGF-beta type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2. Oncogene. 2002;21(51):7883-90.
Alcock, R. A., Dey, S., Chendil, D., Inayat, M. S., Mohiuddin, M., Hartman, G., ... Ahmed, M. M. (2002). Farnesyltransferase inhibitor (L-744,832) restores TGF-beta type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2. Oncogene, 21(51), pp. 7883-90.
Alcock RA, et al. Farnesyltransferase Inhibitor (L-744,832) Restores TGF-beta Type II Receptor Expression and Enhances Radiation Sensitivity in K-ras Mutant Pancreatic Cancer Cell Line MIA PaCa-2. Oncogene. 2002 Nov 7;21(51):7883-90. PubMed PMID: 12420225.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Farnesyltransferase inhibitor (L-744,832) restores TGF-beta type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2. AU - Alcock,Rachael A, AU - Dey,Swatee, AU - Chendil,Damodaran, AU - Inayat,Mohammed S, AU - Mohiuddin,Mohammed, AU - Hartman,George, AU - Chatfield,Lee K, AU - Gallicchio,Vincent S, AU - Ahmed,Mansoor M, PY - 2002/01/28/received PY - 2002/07/31/revised PY - 2002/08/07/accepted PY - 2002/11/7/pubmed PY - 2002/12/13/medline PY - 2002/11/7/entrez SP - 7883 EP - 90 JF - Oncogene JO - Oncogene VL - 21 IS - 51 N2 - Activated ras is known to dysregulate TGF-beta signaling by altering the expression of TGF-beta type II receptor (RII). It is well documented that tumor cells harboring mutant ras are more resistant to radiation than cells with wild-type ras. In this study, we hypothesized that the use of farnesyltransferase inhibitor (FTI, L-744,832) may directly restore TGF-beta signaling through RII expression via ras dependent or independent pathway leading to induction of radiation sensitivity. Two pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2 were used in this study. FTI inhibited farnesylation of Ras protein more significantly in MIA PaCa-2 than BxPC-3 cells. In contrast, MIA PaCa-2 cells were resistant to radiation when compared to BxPC-3 cells. BxPC-3 cells were more resistant to FTI than MIA PaCa-2 cells. In combination treatment, no significant radiosensitizing effect of FTI was observed in BxPC-3 cells at 5 or 10 microM. However, in MIA PaCa-2 cells, a significant radiosensitizing effect was observed at both 5 and 10 microM concentrations (P>0.004). The TGF-beta effector gene p21(waf1/cip1) was elevated in combination treatment in MIA PaCa-2 but not in BxPC-3 cells. In MIA PaCa-2 cells, FTI induced TGF-beta responsive promoter activity as assessed by 3TP-luciferase activity. A further induction of luciferase activity was observed in MIA PaCa-2 cells treated with radiation and FTI. Induction of TGF-beta signaling by FTI was mediated through restoration of the RII expression, as demonstrated by RT-PCR analysis. In addition, re-expression of RII by FTI was associated with a decrease in DNA methyltransferase 1 (DNMT1) levels. Thus, these findings suggest that the L-744,832 treatment restores the RII expression through inhibition of DNMT1 levels causing induction of TGF-beta signaling by radiation and this forms a novel molecular mechanism of radiosensitization by FTI. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/12420225/Farnesyltransferase_inhibitor__L_744832__restores_TGF_beta_type_II_receptor_expression_and_enhances_radiation_sensitivity_in_K_ras_mutant_pancreatic_cancer_cell_line_MIA_PaCa_2_ L2 - http://dx.doi.org/10.1038/sj.onc.1205948 DB - PRIME DP - Unbound Medicine ER -