Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of nf-κb activation

Xiaolin Hu, Mary A. Zimmerman, Kankana Bardhan, Dafeng Yang, Jennifer L Waller, Georgia B. Liles, Jeffrey R Lee, Raphael Pollock, Dina Lev, Carl F. Ware, Ellen Garber, Veronique Bailly, Jeffrey L. Browning, Kebin Liu

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19 Citations (Scopus)

Abstract

Ligation of the lymphotoxin β receptor (LTβR) has been shown to induce both tumor growth inhibition and promotion. The functions of LTβR in these two contrasting cellular processes require further study. We demonstrated here that mice deficient in LTβR ligands, LTα, LIGHT or both LTβ and LIGHT, exhibit greater susceptibility to methylcholanthrene-induced tumor development. LTα, LTβ and LIGHT were expressed in tumor-infiltrating immune cells, and LTβR was expressed on human colon carcinoma and soft tissue sarcoma (STS) cells. Human LTβR agonist monoclonal antibody (mAb) BS-1 induced both growth inhibition and NF-κB activation in human colon carcinoma, mammary carcinoma and STS cells. Interestingly, BS-1 also significantly inhibited growth of doxorubicin-resistant and radiation-resistant human STS cells in vitro. In the molecular mechanism level, we demonstrated that BS-1 induces caspases 8 and 3 activation and cytochrome c release in tumor cells, suggesting that the LTβR mediates apoptosis at least partially through a caspase-dependent mechanism. Furthermore, mouse LTβR mAb ACH6 suppressed colon carcinoma cell metastatic potential in an experimental metastasis mouse model. Although blocking NF-κB activation did not alter tumor cell growth rate and tumor cell response to LTβR mAb-induced growth inhibition in vitro, surprisingly, blocking NF-κB activation significantly enhanced colon carcinoma cell metastatic potential in vivo, suggesting that the LTβR-mediated apoptosis pathway and NF-κB signaling pathway might cooperate to suppress tumor growth in vivo. In summary, our findings determine that LTβR mediates tumor cell apoptosis in colon carcinoma, mammary carcinoma and sarcoma and that LTβR-activated NF-κB potentially functions as a tumor suppressor.

Original languageEnglish (US)
Pages (from-to)1105-1114
Number of pages10
JournalCarcinogenesis
Volume34
Issue number5
DOIs
StatePublished - May 1 2013

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Lymphotoxin-alpha
Caspases
Apoptosis
Neoplasms
Colon
Sarcoma
Carcinoma
Growth
Monoclonal Antibodies
Light
In Vitro Techniques
Breast Neoplasms
Methylcholanthrene
Caspase 8
Cytochromes c
Caspase 3
Doxorubicin
Ligation

ASJC Scopus subject areas

  • Cancer Research

Cite this

Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of nf-κb activation. / Hu, Xiaolin; Zimmerman, Mary A.; Bardhan, Kankana; Yang, Dafeng; Waller, Jennifer L; Liles, Georgia B.; Lee, Jeffrey R; Pollock, Raphael; Lev, Dina; Ware, Carl F.; Garber, Ellen; Bailly, Veronique; Browning, Jeffrey L.; Liu, Kebin.

In: Carcinogenesis, Vol. 34, No. 5, 01.05.2013, p. 1105-1114.

Research output: Contribution to journalArticle

Hu, X, Zimmerman, MA, Bardhan, K, Yang, D, Waller, JL, Liles, GB, Lee, JR, Pollock, R, Lev, D, Ware, CF, Garber, E, Bailly, V, Browning, JL & Liu, K 2013, 'Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of nf-κb activation', Carcinogenesis, vol. 34, no. 5, pp. 1105-1114. https://doi.org/10.1093/carcin/bgt014
Hu, Xiaolin ; Zimmerman, Mary A. ; Bardhan, Kankana ; Yang, Dafeng ; Waller, Jennifer L ; Liles, Georgia B. ; Lee, Jeffrey R ; Pollock, Raphael ; Lev, Dina ; Ware, Carl F. ; Garber, Ellen ; Bailly, Veronique ; Browning, Jeffrey L. ; Liu, Kebin. / Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of nf-κb activation. In: Carcinogenesis. 2013 ; Vol. 34, No. 5. pp. 1105-1114.
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abstract = "Ligation of the lymphotoxin β receptor (LTβR) has been shown to induce both tumor growth inhibition and promotion. The functions of LTβR in these two contrasting cellular processes require further study. We demonstrated here that mice deficient in LTβR ligands, LTα, LIGHT or both LTβ and LIGHT, exhibit greater susceptibility to methylcholanthrene-induced tumor development. LTα, LTβ and LIGHT were expressed in tumor-infiltrating immune cells, and LTβR was expressed on human colon carcinoma and soft tissue sarcoma (STS) cells. Human LTβR agonist monoclonal antibody (mAb) BS-1 induced both growth inhibition and NF-κB activation in human colon carcinoma, mammary carcinoma and STS cells. Interestingly, BS-1 also significantly inhibited growth of doxorubicin-resistant and radiation-resistant human STS cells in vitro. In the molecular mechanism level, we demonstrated that BS-1 induces caspases 8 and 3 activation and cytochrome c release in tumor cells, suggesting that the LTβR mediates apoptosis at least partially through a caspase-dependent mechanism. Furthermore, mouse LTβR mAb ACH6 suppressed colon carcinoma cell metastatic potential in an experimental metastasis mouse model. Although blocking NF-κB activation did not alter tumor cell growth rate and tumor cell response to LTβR mAb-induced growth inhibition in vitro, surprisingly, blocking NF-κB activation significantly enhanced colon carcinoma cell metastatic potential in vivo, suggesting that the LTβR-mediated apoptosis pathway and NF-κB signaling pathway might cooperate to suppress tumor growth in vivo. In summary, our findings determine that LTβR mediates tumor cell apoptosis in colon carcinoma, mammary carcinoma and sarcoma and that LTβR-activated NF-κB potentially functions as a tumor suppressor.",
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T1 - Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of nf-κb activation

AU - Hu, Xiaolin

AU - Zimmerman, Mary A.

AU - Bardhan, Kankana

AU - Yang, Dafeng

AU - Waller, Jennifer L

AU - Liles, Georgia B.

AU - Lee, Jeffrey R

AU - Pollock, Raphael

AU - Lev, Dina

AU - Ware, Carl F.

AU - Garber, Ellen

AU - Bailly, Veronique

AU - Browning, Jeffrey L.

AU - Liu, Kebin

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Ligation of the lymphotoxin β receptor (LTβR) has been shown to induce both tumor growth inhibition and promotion. The functions of LTβR in these two contrasting cellular processes require further study. We demonstrated here that mice deficient in LTβR ligands, LTα, LIGHT or both LTβ and LIGHT, exhibit greater susceptibility to methylcholanthrene-induced tumor development. LTα, LTβ and LIGHT were expressed in tumor-infiltrating immune cells, and LTβR was expressed on human colon carcinoma and soft tissue sarcoma (STS) cells. Human LTβR agonist monoclonal antibody (mAb) BS-1 induced both growth inhibition and NF-κB activation in human colon carcinoma, mammary carcinoma and STS cells. Interestingly, BS-1 also significantly inhibited growth of doxorubicin-resistant and radiation-resistant human STS cells in vitro. In the molecular mechanism level, we demonstrated that BS-1 induces caspases 8 and 3 activation and cytochrome c release in tumor cells, suggesting that the LTβR mediates apoptosis at least partially through a caspase-dependent mechanism. Furthermore, mouse LTβR mAb ACH6 suppressed colon carcinoma cell metastatic potential in an experimental metastasis mouse model. Although blocking NF-κB activation did not alter tumor cell growth rate and tumor cell response to LTβR mAb-induced growth inhibition in vitro, surprisingly, blocking NF-κB activation significantly enhanced colon carcinoma cell metastatic potential in vivo, suggesting that the LTβR-mediated apoptosis pathway and NF-κB signaling pathway might cooperate to suppress tumor growth in vivo. In summary, our findings determine that LTβR mediates tumor cell apoptosis in colon carcinoma, mammary carcinoma and sarcoma and that LTβR-activated NF-κB potentially functions as a tumor suppressor.

AB - Ligation of the lymphotoxin β receptor (LTβR) has been shown to induce both tumor growth inhibition and promotion. The functions of LTβR in these two contrasting cellular processes require further study. We demonstrated here that mice deficient in LTβR ligands, LTα, LIGHT or both LTβ and LIGHT, exhibit greater susceptibility to methylcholanthrene-induced tumor development. LTα, LTβ and LIGHT were expressed in tumor-infiltrating immune cells, and LTβR was expressed on human colon carcinoma and soft tissue sarcoma (STS) cells. Human LTβR agonist monoclonal antibody (mAb) BS-1 induced both growth inhibition and NF-κB activation in human colon carcinoma, mammary carcinoma and STS cells. Interestingly, BS-1 also significantly inhibited growth of doxorubicin-resistant and radiation-resistant human STS cells in vitro. In the molecular mechanism level, we demonstrated that BS-1 induces caspases 8 and 3 activation and cytochrome c release in tumor cells, suggesting that the LTβR mediates apoptosis at least partially through a caspase-dependent mechanism. Furthermore, mouse LTβR mAb ACH6 suppressed colon carcinoma cell metastatic potential in an experimental metastasis mouse model. Although blocking NF-κB activation did not alter tumor cell growth rate and tumor cell response to LTβR mAb-induced growth inhibition in vitro, surprisingly, blocking NF-κB activation significantly enhanced colon carcinoma cell metastatic potential in vivo, suggesting that the LTβR-mediated apoptosis pathway and NF-κB signaling pathway might cooperate to suppress tumor growth in vivo. In summary, our findings determine that LTβR mediates tumor cell apoptosis in colon carcinoma, mammary carcinoma and sarcoma and that LTβR-activated NF-κB potentially functions as a tumor suppressor.

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