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Restoration of transforming growth factor-beta signaling enhances radiosensitivity by altering the Bcl-2/Bax ratio in the p53 mutant pancreatic cancer cell line MIA PaCa-2.
J Biol Chem 2002; 277(3):2234-46JB

Abstract

In this study, we investigated whether lack of transforming growth factor beta (TGF-beta) type II receptor (RII) expression and loss of TGF-beta signaling played a role in radiation resistance of pancreatic cancer cells MIA PaCa-2 that possess a mutated p53 gene. Transfection of this cell line with a RII cDNA led to a stimulation of the transcriptional activity of p3TP-Lux, a TGF-beta-responsive reporter construct. The RII transfectants (MIA PaCa-2/RII) showed a significant increase in sensitivity to radiation when compared with MIA PaCa-2/vector cells. The increase in sensitivity to radiation was reversed by neutralizing antibodies to TGF-beta, indicating that these changes were dependent on TGF-beta signaling. Compared with MIA PaCa-2/vector cells, MIA PaCa-2/RII cells showed a greater than 3-fold increase in apoptosis after radiation. Enhanced radiation sensitivity of MIA PaCa-2/RII cells was associated with an induction of Bax mRNA and protein that was followed by a release of cytochrome c and activation of caspase-3 and poly(ADP-ribose) polymerase cleavage after radiation exposure. Overexpression of Bcl-x(L) or treatment with antisense oligodeoxynucleotides targeted against Bax significantly inhibited radiation-induced apoptosis in MIA PaCa-2/RII but not in MIA PaCa-2/Vector cells, suggesting that Bax induction is necessary for radiation-induced TGF-beta signaling-mediated apoptosis. Thus, restoration of TGF-beta signaling sensitized these cells to ionizing radiation, although these cells possess a mutated p53 gene. In addition, disruption of RII function by dominant negative mutant of RII inhibited the radiation-induced TGF-beta signaling and apoptosis in primary cultures of mouse embryonic fibroblasts. Together, these observations imply that RII is an important component of radiation-induced TGF-beta signaling, and loss of function of RII may enhance resistance to radiation-induced apoptosis.

Authors+Show Affiliations

Department of Radiation Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11694525

Citation

Ahmed, Mansoor M., et al. "Restoration of Transforming Growth Factor-beta Signaling Enhances Radiosensitivity By Altering the Bcl-2/Bax Ratio in the P53 Mutant Pancreatic Cancer Cell Line MIA PaCa-2." The Journal of Biological Chemistry, vol. 277, no. 3, 2002, pp. 2234-46.
Ahmed MM, Alcock RA, Chendil D, et al. Restoration of transforming growth factor-beta signaling enhances radiosensitivity by altering the Bcl-2/Bax ratio in the p53 mutant pancreatic cancer cell line MIA PaCa-2. J Biol Chem. 2002;277(3):2234-46.
Ahmed, M. M., Alcock, R. A., Chendil, D., Dey, S., Das, A., Venkatasubbarao, K., ... Freeman, J. W. (2002). Restoration of transforming growth factor-beta signaling enhances radiosensitivity by altering the Bcl-2/Bax ratio in the p53 mutant pancreatic cancer cell line MIA PaCa-2. The Journal of Biological Chemistry, 277(3), pp. 2234-46.
Ahmed MM, et al. Restoration of Transforming Growth Factor-beta Signaling Enhances Radiosensitivity By Altering the Bcl-2/Bax Ratio in the P53 Mutant Pancreatic Cancer Cell Line MIA PaCa-2. J Biol Chem. 2002 Jan 18;277(3):2234-46. PubMed PMID: 11694525.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Restoration of transforming growth factor-beta signaling enhances radiosensitivity by altering the Bcl-2/Bax ratio in the p53 mutant pancreatic cancer cell line MIA PaCa-2. AU - Ahmed,Mansoor M, AU - Alcock,Rachael A, AU - Chendil,Damodaran, AU - Dey,Swatee, AU - Das,Anindita, AU - Venkatasubbarao,Kolaparthi, AU - Mohiuddin,Mohammed, AU - Sun,LuZhe, AU - Strodel,William E, AU - Freeman,James W, Y1 - 2001/11/01/ PY - 2001/11/6/pubmed PY - 2002/2/14/medline PY - 2001/11/6/entrez SP - 2234 EP - 46 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 3 N2 - In this study, we investigated whether lack of transforming growth factor beta (TGF-beta) type II receptor (RII) expression and loss of TGF-beta signaling played a role in radiation resistance of pancreatic cancer cells MIA PaCa-2 that possess a mutated p53 gene. Transfection of this cell line with a RII cDNA led to a stimulation of the transcriptional activity of p3TP-Lux, a TGF-beta-responsive reporter construct. The RII transfectants (MIA PaCa-2/RII) showed a significant increase in sensitivity to radiation when compared with MIA PaCa-2/vector cells. The increase in sensitivity to radiation was reversed by neutralizing antibodies to TGF-beta, indicating that these changes were dependent on TGF-beta signaling. Compared with MIA PaCa-2/vector cells, MIA PaCa-2/RII cells showed a greater than 3-fold increase in apoptosis after radiation. Enhanced radiation sensitivity of MIA PaCa-2/RII cells was associated with an induction of Bax mRNA and protein that was followed by a release of cytochrome c and activation of caspase-3 and poly(ADP-ribose) polymerase cleavage after radiation exposure. Overexpression of Bcl-x(L) or treatment with antisense oligodeoxynucleotides targeted against Bax significantly inhibited radiation-induced apoptosis in MIA PaCa-2/RII but not in MIA PaCa-2/Vector cells, suggesting that Bax induction is necessary for radiation-induced TGF-beta signaling-mediated apoptosis. Thus, restoration of TGF-beta signaling sensitized these cells to ionizing radiation, although these cells possess a mutated p53 gene. In addition, disruption of RII function by dominant negative mutant of RII inhibited the radiation-induced TGF-beta signaling and apoptosis in primary cultures of mouse embryonic fibroblasts. Together, these observations imply that RII is an important component of radiation-induced TGF-beta signaling, and loss of function of RII may enhance resistance to radiation-induced apoptosis. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11694525/Restoration_of_transforming_growth_factor_beta_signaling_enhances_radiosensitivity_by_altering_the_Bcl_2/Bax_ratio_in_the_p53_mutant_pancreatic_cancer_cell_line_MIA_PaCa_2_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11694525 DB - PRIME DP - Unbound Medicine ER -