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Adipocyte microenvironment promotes Bclxl expression and confers chemoresistance in ovarian cancer cells

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Abstract

Resistance to mitochondria-initiated apoptosis is a hallmark of chemoresistant cancer stem cells including CD44+/MyD88+ epithelial ovarian cancer (EOC) stem cells. This is controlled by members of the Bcl2 family of proteins, which function as rheostats of mitochondrial stability. We observed a differential expression profile of Bcl2 family members comparing the chemoresistant EOC stem cells and the chemosensitive CD44−/MyD88− EOC cells. Chemoresistant EOC stem cells surprisingly express higher levels of the pro-apoptotic members Bak and Bax compared to the chemosensitive EOC cells. In addition, whereas chemosensitive EOC cells preferentially express Bcl2, chemoresistant EOC stem cells preferentially express Bclxl. In the EOC stem cells, 40% knock-down of Bclxl expression was sufficient to induce the full activation of caspases and this can be reversed by concurrent knock-down of Puma. More importantly, we demonstrate that Bclxl expression levels in EOC cells is dynamic and can be regulated by microenvironments that are enriched with the pro-inflammatory cytokine IL-6 such as the cancer stem cell and adipocyte niches. Adipocyte-induced upregulation of Bclxl correlated with acquisition of chemoresistance and thus demonstrates how a specific microenvironment can regulate the expression of apoptotic proteins and confer chemoresistance.

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Authors and Affiliations

  1. Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St. LSOG 305A, New Haven, CT, 06520, USA

    Carlos Cardenas, Michele K. Montagna, Mary Pitruzzello, Eydis Lima, Gil Mor & Ayesha B. Alvero

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  1. Carlos Cardenas
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  2. Michele K. Montagna
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  3. Mary Pitruzzello
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  4. Eydis Lima
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  5. Gil Mor
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  6. Ayesha B. Alvero
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Correspondence to Gil Mor.

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This work is supported in part by a grant from the Discovery to Cure Program, the Sands Family Foundation, and Debra Levin Endowment Fund.

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Cardenas, C., Montagna, M.K., Pitruzzello, M. et al. Adipocyte microenvironment promotes Bclxl expression and confers chemoresistance in ovarian cancer cells. Apoptosis 22, 558–569 (2017). https://doi.org/10.1007/s10495-016-1339-x

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