Format

Send to

Choose Destination
Cell Death Dis. 2017 Sep 14;8(9):e3049. doi: 10.1038/cddis.2017.444.

Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
2
Bioorganic and Medicinal Chemistry Research Center, School of Pharmaceutical Sciences, Wenzhou Medical College, Wenzhou 325035, China.
3
Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing 210093, China.

Abstract

Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca2+ from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity. The disruption of calcium homeostasis induced ER stress, leading to apoptosis. More importantly, the elevated intracellular calcium signals induced autophagy through the activation of the CaMKK-AMPK-mTOR pathway and mitochondrial damage. In two TNBC xenograft mouse models, RL71 also displayed strong efficacy including the inhibition of tumor growth, the reduction of metastasis, as well as the prolongation of survival time. These findings suggest SERCA2 as a previous unknown target candidate for TNBC treatment and support the idea that autophagy inducers could be useful as new therapeutics in TNBC treatment.

PMID:
28906486
PMCID:
PMC5636988
DOI:
10.1038/cddis.2017.444
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center