Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer

Michelle Bowie, Patrick Pilie, Julia Wulfkuhle, Siya Lem, Abigail Hoffman, Shraddha Desai, Emanuel Petricoin, Amira Carter, Adrian Ambrose, Victoria Seewaldt, Dihua Yu, Catherine Ibarra Drendall*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

34 Scopus citations


AIM: To investigate the mechanism of action of lipophilic antidepressant fluoxetine (FLX) in representative molecular subtypes of breast cancer. METHODS: The anti-proliferative effects and mechanistic action of FLX in triple-negative (SUM149PT) and luminal (T47D and Au565) cancer cells and nontransformed MCF10A were investigated. Reverse phase protein microarray (RPPM) was performed with and without 10 μmol/L FLX for 24 and 48 h to determine which proteins are significantly changed. Viability and cell cycle analysis were also performed to determine drug effects on cell growth. Western blotting was used to confirm the change in protein expression examined by RPPM or pursue other signaling proteins. RESULTS: The FLX-induced cell growth inhibition in all cell lines was concentration- and time-dependent but less pronounced in early passage MCF10A. In comparison to the other lines, cell growth reduction in SUM149PT coincided with significant induction of endoplasmic reticulum (ER) stress and autophagy after 24 and 48 h of 10 μmol/L FLX, resulting in decreased translation of proteins along the receptor tyrosine kinase/Akt/mammalian target of rapamycin pathways. The increase in autophagy marker, cleaved microtubule-associated protein 1 light chain 3, in SUM149PT after 24 h of FLX was likely due to increased metabolic demands of rapidly dividing cells and ER stress. Consequently, the unfolded protein response mediated by double-stranded RNA-dependent protein kinase-like ER kinase resulted in inhibition of protein synthesis, growth arrest at the G1 phase, autophagy, and caspase-7-mediated cell death. CONCLUSION: Our study suggests a new role for FLX as an inducer of ER stress and autophagy, resulting in death of aggressive triple negative breast cancer SUM149PT.

Original languageEnglish
Pages (from-to)299-311
Number of pages13
JournalWorld Journal of Clinical Oncology
Issue number6
StatePublished - 10 Dec 2015
Externally publishedYes


  • Apoptosis
  • Autophagy
  • Endoplasmic reticulum stress
  • Fluoxetine
  • Inflammatory breast cancer


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