Oncotarget

Research Papers:

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, Roberta L. Tanguay, Xiao-Kun Zhang and Siva Kumar Kolluri _

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Oncotarget. 2018; 9:26072-26085. https://doi.org/10.18632/oncotarget.25437

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Abstract

Martin C. Pearce1, John T. Gamble1,2, Prasad R. Kopparapu1, Edmond F. O'Donnell1, Monica J. Mueller1, Hyo Sang Jang1, Julie A. Greenwood2, Arnold C. Satterthwait3, Robert L. Tanguay4,5,6, Xiao-Kun Zhang3 and Siva Kumar Kolluri1,4,5,6

1Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA

2Department of Biochemistry & Biophysics, Oregon State University, Corvallis, Oregon 97331, USA

3Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92031, USA

4Department of Environmental & Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA

5Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA

6Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR 97331, USA

Correspondence to:

Siva Kumar Kolluri, email: siva.kolluri@oregonstate.edu

Keywords: chemoresistance; Bcl-2; NuBCP-9; paclitaxel; lung cancer

Received: February 19, 2018     Accepted: April 24, 2018     Published: May 25, 2018

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.


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