Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers
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Michelle M. Williams1, David L. Elion1, Bushra Rahman2, Donna J. Hicks2, Violeta Sanchez3 and Rebecca S. Cook1,2,4,5
1 Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
2 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA
3 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
4 Department of Biomedical Engineering, Vanderbilt University, Nashville TN 37232, USA
5 The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
|Rebecca S. Cook,||email:||Rebecca.firstname.lastname@example.org|
Keywords: Mcl-1; ABT-263 resistance; mTORC1 signaling; luminal breast cancers
Received: April 23, 2019 Accepted: June 14, 2019 Published: September 10, 2019
Cancers often overexpress anti-apoptotic Bcl-2 proteins for cell death evasion, a recognized hallmark of cancer progression. While estrogen receptor (ER)-α+ breast cancers express high levels of three anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1), pharmacological inhibition of Bcl-2 and/or Bcl-xL fails to induce cell death in ERα+ breast cancer cell lines, due to rapid and robust Mcl-1 upregulation. The mechanisms of acute Mcl-1 upregulation in response to Bcl-2/Bcl-xL inhibition remain undefined in in ERα+ breast cancers. We report here that blockade of Bcl-2 or Bcl-xL, alone or together, rapidly induced mTOR signaling in ERα+ breast cancer cells, rapidly increasing cap-dependent Mcl-1 translation. Cells treated with a pharmacological inhibitor of cap-dependent translation, or with the mTORC1 inhibitor RAD001/everolimus, displayed reduced protein levels of Mcl-1 under basal conditions, and failed to upregulate Mcl-1 protein expression following treatment with ABT-263, a pharmacological inhibitor of Bcl-2 and Bcl-xL. Although treatment with ABT-263 alone did not sustain apoptosis in tumor cells in culture or in vivo, ABT-263 plus RAD001 increased apoptosis to a greater extent than either agent used alone. Similarly, combined use of the selective Mcl-1 inhibitor VU661013 with ABT-263 resulted in tumor cell apoptosis and diminished tumor growth in vivo. These findings suggest that rapid Mcl-1 translation drives ABT-263 resistance, but can be combated directly using emerging Mcl-1 inhibitors, or indirectly through existing and approved mTOR inhibitors.
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