Unknown

Dataset Information

0

Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers.


ABSTRACT: Cancers often overexpress anti-apoptotic Bcl-2 proteins for cell death evasion, a recognized hallmark of cancer progression. While estrogen receptor (ER)-?+ 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 ER?+ 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 ER?+ breast cancers. We report here that blockade of Bcl-2 or Bcl-xL, alone or together, rapidly induced mTOR signaling in ER?+ 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.

SUBMITTER: Williams MM 

PROVIDER: S-EPMC6739218 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers.

Williams Michelle M MM   Elion David L DL   Rahman Bushra B   Hicks Donna J DJ   Sanchez Violeta V   Cook Rebecca S RS  

Oncotarget 20190901 52


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 inhibitio  ...[more]

Similar Datasets

| S-EPMC7744368 | biostudies-literature
| S-EPMC4980485 | biostudies-literature
2005-12-01 | GSE2740 | GEO
| S-EPMC6756023 | biostudies-literature
| S-EPMC5548489 | biostudies-literature
| S-EPMC4891027 | biostudies-literature
| S-EPMC8327620 | biostudies-literature
| S-EPMC4301951 | biostudies-literature
| S-EPMC7357313 | biostudies-literature
| S-EPMC3100231 | biostudies-literature