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Proteasome Inhibition Increases Interleukin‐8 Expression in Triple Negative Breast Cancer Cells, Resulting in Their Increased Survival, Proliferation, and Migration
Author(s) -
Uddin Mohammad,
Zou Yue,
Gaire Bijaya,
Padmanabhan Sveta,
Vancurova Ivana
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.647.45
Subject(s) - triple negative breast cancer , cancer research , bortezomib , proteasome , proteasome inhibitor , cell growth , interleukin 8 , breast cancer , medicine , cancer , biology , immunology , cytokine , multiple myeloma , microbiology and biotechnology , genetics
Interleukin‐8 (IL‐8, CXCL8) is a pro‐inflammatory and pro‐angiogenic chemokine that stimulates cancer progression by inducing tumor cell proliferation, survival, and migration. IL‐8 expression is increased in many types of advanced cancers, including triple negative breast cancer (TNBC), and correlates with poor prognosis. Because no targeted therapies are currently available, and majority of TNBC patients initially responding to cytotoxic chemotherapy become drug‐resistant, development of novel therapeutic strategies is essential. Proteasome inhibition by Bortezomib (BZ; Velcade; PS‐341) and Carfilzomib (CZ), developed for its ability to inhibit transcription of NFκB‐dependent anti‐apoptotic genes, has been effective in treating hematological malignancies. By contrast, as single agents, proteasome inhibitors (PI) have failed to show a significant clinical activity in solid tumors, including TNBC, but the mechanisms are not fully understood. Here, we demonstrate that proteasome inhibition increases expression of IL‐8, resulting in increased survival, proliferation, and migration of TNBC cells. The induced IL‐8 expression is mediated by IkB kinase (IKK), and associated with an increased nuclear accumulation of p65 NFκB, and IKK‐dependent p65 recruitment to IL‐8 promoter. Inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ‐treated TNBC cells. These results are the first to show that proteasome inhibition increases IL‐8 signaling in TNBC cells, suggesting that targeting IKK activity might increase PI effectiveness in TNBC treatment. Support or Funding Information Sponsor : Dr. Ivana Vancurova (ASBMB member ID: 32743) Funding : NIH CA202775 grant (to Dr. Ivana Vancurova) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .