Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells

Martin C. Pearce; John T. Gamble; Prasad R. Kopparapu; Edmond F. O'Donnell; Monica J. Mueller; Hyo Sang Jang; Julie A. Greenwood; Arnold C. Satterthwait; Robert L. Tanguay; Xiao Kun Zhang; Siva Kumar Kolluri

doi:10.18632/oncotarget.25437

Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells

Martin C. Pearce, John T. Gamble, Prasad R. Kopparapu, Edmond F. O'Donnell, Monica J. Mueller, Hyo Sang Jang, Julie A. Greenwood, Arnold C. Satterthwait, Robert L. Tanguay, Xiao Kun Zhang, Siva Kumar Kolluri

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33 Scopus citations

Abstract

Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2.

Original language	English (US)
Pages (from-to)	26072-26085
Number of pages	14
Journal	Oncotarget
Volume	9
Issue number	40
DOIs	https://doi.org/10.18632/oncotarget.25437
State	Published - 2018
Externally published	Yes

Keywords

Bcl-2
Chemoresistance
Lung cancer
NuBCP-9
Paclitaxel

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.25437

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Pearce, M. C., Gamble, J. T., Kopparapu, P. R., O'Donnell, E. F., Mueller, M. J., Jang, H. S., Greenwood, J. A., Satterthwait, A. C., Tanguay, R. L., Zhang, X. K., & Kolluri, S. K. (2018). Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells. Oncotarget, 9(40), 26072-26085. https://doi.org/10.18632/oncotarget.25437

Pearce, MC, Gamble, JT, Kopparapu, PR, O'Donnell, EF, Mueller, MJ, Jang, HS, Greenwood, JA, Satterthwait, AC, Tanguay, RL, Zhang, XK & Kolluri, SK 2018, 'Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells', Oncotarget, vol. 9, no. 40, pp. 26072-26085. https://doi.org/10.18632/oncotarget.25437

@article{3487169749814ee3a4a53ff9113e5594,

title = "Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells",

abstract = "Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2.",

keywords = "Bcl-2, Chemoresistance, Lung cancer, NuBCP-9, Paclitaxel",

author = "Pearce, {Martin C.} and Gamble, {John T.} and Kopparapu, {Prasad R.} and O'Donnell, {Edmond F.} and Mueller, {Monica J.} and Jang, {Hyo Sang} and Greenwood, {Julie A.} and Satterthwait, {Arnold C.} and Tanguay, {Robert L.} and Zhang, {Xiao Kun} and Kolluri, {Siva Kumar}",

note = "Funding Information: This work was supported in part by grants from the US Army Medical Research and Material Command (W81XWH-08-1-0600 and W81XWH-12-1-0069), American Cancer Society (RSG-13-132-01-CDD), National Institutes of Health (5RO1ES016651) and Oregon State University Venture Development Fund (http://advantage.oregonstate.edu/funding-opportunities). Funding Information: We thank Jonathan M. Avery, Cathy Duong, Stephen En-han Oh, Brenna L. Stevens for excellent technical assistance, the staff at the Oregon State University Sinnhuber Aquatic Research Laboratory for animal husbandry support, Allison K. Ehrlich for help with Flow Cytometry experiments and Veronica Puig-Sanvicens, Andrew Buermeyer for helpful discussions. This work was supported in part by grants from the US Army Medical Research and Material Command (W81XWH-08-1-0600 and W81XWH-12-1-0069), American Cancer Society (RSG-13-132-01-CDD), National Institutes of Health (5RO1ES016651) and Oregon State University Venture Development Fund (http://advantage.oregonstate.edu/funding-opportunities). Publisher Copyright: {\textcopyright} Pearce et al.",

year = "2018",

doi = "10.18632/oncotarget.25437",

language = "English (US)",

volume = "9",

pages = "26072--26085",

journal = "Oncotarget",

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number = "40",

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T1 - Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells

AU - Pearce, Martin C.

AU - Gamble, John T.

AU - Kopparapu, Prasad R.

AU - O'Donnell, Edmond F.

AU - Mueller, Monica J.

AU - Jang, Hyo Sang

AU - Greenwood, Julie A.

AU - Satterthwait, Arnold C.

AU - Tanguay, Robert L.

AU - Zhang, Xiao Kun

AU - Kolluri, Siva Kumar

N1 - Funding Information: This work was supported in part by grants from the US Army Medical Research and Material Command (W81XWH-08-1-0600 and W81XWH-12-1-0069), American Cancer Society (RSG-13-132-01-CDD), National Institutes of Health (5RO1ES016651) and Oregon State University Venture Development Fund (http://advantage.oregonstate.edu/funding-opportunities). Funding Information: We thank Jonathan M. Avery, Cathy Duong, Stephen En-han Oh, Brenna L. Stevens for excellent technical assistance, the staff at the Oregon State University Sinnhuber Aquatic Research Laboratory for animal husbandry support, Allison K. Ehrlich for help with Flow Cytometry experiments and Veronica Puig-Sanvicens, Andrew Buermeyer for helpful discussions. This work was supported in part by grants from the US Army Medical Research and Material Command (W81XWH-08-1-0600 and W81XWH-12-1-0069), American Cancer Society (RSG-13-132-01-CDD), National Institutes of Health (5RO1ES016651) and Oregon State University Venture Development Fund (http://advantage.oregonstate.edu/funding-opportunities). Publisher Copyright: © Pearce et al.

PY - 2018

Y1 - 2018

N2 - Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2.

AB - Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2.

KW - Bcl-2

KW - Chemoresistance

KW - Lung cancer

KW - NuBCP-9

KW - Paclitaxel

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JF - Oncotarget

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ER -

Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells

Abstract

Keywords

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