Restoration of Transforming Growth Factor-β Signaling Enhances Radiosensitivity by Altering the Bcl-2/Bax Ratio in the p53 Mutant Pancreatic Cancer Cell Line MIA PaCa-2

Ahmed, Mansoor M.; Alcock, Rachael A.; Damodaran, Chendil; Dey, Swatee; Das, Anindita; Venkatasubbarao, Kolaparthi; Mohiuddin, Mohammed; Sun, LuZhe; Strodel, William E.; Freeman, James W.

doi:10.1074/jbc.m110168200

Cited by 56 publications

(51 citation statements)

References 52 publications

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“…Based on exclusive induction of TGF-β1 by radiation and its implication on negative growth regulation and apoptosis, we hypothesized that radiation induces endogenous TGF-β protein that will exert clonogenic inhibition and cause apoptosis in cells with intact TGF-β signaling components. This hypothesis was demonstrated and proved by our group earlier (17,18).…”

Section: Introductionsupporting

confidence: 54%

“…We have previously reported that restoration of TGF-β signaling enhances sensitivity to ionizing radiation in pancreatic cancer background (17). In the same study, we reported that in pancreatic cancer cell line, MIA PaCa-2, radiation induces TGF-β signaling, up-regulates p21 waf1/cip1 , Bax and activates caspases (17).…”

Section: Introductionmentioning

confidence: 75%

“…In the same study, we reported that in pancreatic cancer cell line, MIA PaCa-2, radiation induces TGF-β signaling, up-regulates p21 waf1/cip1 , Bax and activates caspases (17). By loss-of-function approach using dominantnegative mutant for RII in normal mouse embryonic fibroblasts, we demonstrated that these fibroblast cells were resistant to radiation-induced apoptosis (17). To address the functional role of radiation-induced TGF-β signaling in normal epithelial background, we selected spontaneously immortalized lung epithelial cell line and disrupted the RII receptor gene and assessed it's impact on radio-sensitivity.…”

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 77%

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Inhibition of Transforming Growth Factor-β Signaling in Normal Lung Epithelial Cells Confers Resistance to Ionizing Radiation

Reeves

Zagurovskaya

Gupta

et al. 2007

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To address the functional role of radiation-induced TGF-β signaling in normal epithelial background, we selected spontaneously immortalized lung epithelial cell line derived from the normal lung tissue of dominant-negative mutant of TGF-β RII (ΔRII) transgenic mouse that expressed conditionally ΔRII under the control of metallothionein promoter (MT-1) and assessed it's impact on radio-sensitivity.Method and Materials-Spontaneously immortalized lung epithelial cell culture (SILECC) was established and all analyses were performed within 50 passages. Colony-forming and TUNEL assays were used to assess the clonogenic inhibition and apoptosis respectively. Western blot analysis was performed to assess the kinetics of p21, bax and RII proteins. TGF-β responsive promoter activity was measured using dual-luciferase reporter assay.Results-Exposure to ZnSO 4 inhibited TGF-β signaling induced either by recombinant TGF-β1 or ionizing radiation. SILECC treated either with ZnSO 4 or neutralizing antibody against TGF-β showed a significant increase in radio-resistance when compared to untreated cells. Furthermore, the expression of the ΔRII inhibited the radiation-induced up-regulation of the TGF-β effector gene p21 waf1/cip1. . Conclusions-Our findings imply that inhibition of radiation-induced TGF-β signaling via abrogation of RII function enhances radio-resistance of the normal lung epithelial cells, and this can be directly attributed to the loss of TGF-β signaling function.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 77%

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Inhibition of Transforming Growth Factor-β Signaling in Normal Lung Epithelial Cells Confers Resistance to Ionizing Radiation

Reeves

Zagurovskaya

Gupta

et al. 2007

International Journal of Radiation Oncology*Biology*Physics

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“…MIA PaCa-2 cells lack RII expression and do not respond to TGF-b. Overexpression of RII in these cells restored TGF-b signaling and conferred enhanced radiation sensitivity (Ahmed et al, 2002). Exposure to FTI L744,832, restored RII expression and TGF-b signaling in MIA PaCa-2 cells, suggesting that inhibition of activating functions of ras by FTI does cause a reversal in TGF-b response.…”

Section: Discussionmentioning

confidence: 87%

Farnesyltransferase inhibitor (L-744,832) restores TGF-β type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2

et al. 2002

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Activated ras is known to dysregulate TGF-b signaling by altering the expression of TGF-b 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,832) may directly restore TGF-b 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 mM. However, in MIA PaCa-2 cells, a significant radiosensitizing effect was observed at both 5 and 10 mM concentrations (P40.004). The TGF-b 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-b 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-b 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-b signaling by radiation and this forms a novel molecular mechanism of radiosensitization by FTI.

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Cell death induced by N‐(4‐hydroxyphenyl)retinamide in human epidermal keratinocytes is modulated by TGF‐β and diminishes during the progression of squamous cell carcinoma

Davies

Paterson

Ganapathy

et al. 2006

Intl Journal of Cancer

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It has been demonstrated that the chemopreventive agent N-(4-hydroxyphenyl)retinamide (4-HPR) induces apoptotic cell death, but recent data has suggested that late stage/recurrent tumours lose their response to 4-HPR-induced cell death by mechanisms that are unknown. Our study investigated the ability of 4-HPR to induce cell death in keratinocyte cell lines that represent different stages of carcinogenesis and the role of TGF-b signalling in the induction of cell death by 4-HPR. We show that treatment of the immortalised keratinocyte cell line HaCaT with 10 -5 M 4-HPR induced cell death by apoptosis and caused an accumulation of cells in the G0/G1 phase of the cell cycle. Using a genetically related series of human skin keratinocytes derived from HaCaT that reflect tumour progression and metastasis in vivo, we demonstrate that 4-HPR-induced cell death and apoptosis is attenuated in the more aggressive tumour cell lines but that a reduced level of response is retained. Response to TGF-b-induced growth inhibition was also reduced in the more aggressive cell lines. Treatment of HaCaT cells with 4-HPR induced TGF-b2 expression and an increase in the amount of active TGF-b in the culture medium. The inhibition of TGF-b signalling attenuated 4-HPR-induced apoptosis and both TGF-b1 and TGF-b2 potentiated 4-HPR-induced apoptosis and enhanced 4-HPR-induced growth inhibition. Our results demonstrate that loss of response to 4-HPR correlates with a loss of response to the growth inhibitory effects of TGF-b and that adjuvant therapies that upregulate TGF-b may enhance the chemopreventive effects of 4-HPR. ' 2006 Wiley-Liss, Inc.

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Restoration of Transforming Growth Factor-β Signaling Enhances Radiosensitivity by Altering the Bcl-2/Bax Ratio in the p53 Mutant Pancreatic Cancer Cell Line MIA PaCa-2

Cited by 56 publications

References 52 publications

Inhibition of Transforming Growth Factor-β Signaling in Normal Lung Epithelial Cells Confers Resistance to Ionizing Radiation

Inhibition of Transforming Growth Factor-β Signaling in Normal Lung Epithelial Cells Confers Resistance to Ionizing Radiation

Farnesyltransferase inhibitor (L-744,832) restores TGF-β type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2

Cell death induced by N‐(4‐hydroxyphenyl)retinamide in human epidermal keratinocytes is modulated by TGF‐β and diminishes during the progression of squamous cell carcinoma

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