GX15-070 (obatoclax) induces apoptosis and inhibits cathepsin D- and L-mediated autophagosomal lysis in antiestrogen-resistant breast cancer cells

Jessica L. Schwartz-Roberts, Ayesha N. Shajahan, Katherine L. Cook, Anni Wärri, Mones Abu-Asab, Robert Clarke

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

In estrogen receptor-positive (ER+) breast cancer cells, BCL2 overexpression contributes to antiestrogen resistance. Direct targeting of the antiapoptotic BCL2 members with GX15-070 (obatoclax), a BH3-mimetic currently in clinical development, is an attractive strategy to overcome antiestrogen resistance in some breast cancers. Recently, GX15-070 has been shown to induce both apoptosis and autophagy, yet the underlying cell death mechanisms have yet to be elucidated. Here, we show that GX15-070 is more effective in reducing the cell density of antiestrogen-resistant breast cancer cells versus sensitive cells and that this increased sensitivity of resistant cells to GX15-070 correlates with an accumulation of autophagic vacuoles. Formation of autophagosomes in GX15-070-treated cells was verified by changes in expression of the lipidation of microtubuleassociated protein-1 light chain-3 and both confocal and transmission electron microscopy. While GX15-070 treatment promotes autophagic vacuole and autolysosome formation, p62/SQSTM1, a marker for autophagic degradation, levels accumulate. Moreover, GX15-070 exposure leads to a reduction in cathepsin D (CTSD) and L (CTSL1) protein expression that would otherwise digest autolysosome cargo. Thus, GX15-070 has dual roles in promoting cell death: (i) directly inhibiting antiapoptotic BCL2 family members, thereby inducing apoptosis; and (ii) inhibiting downstream CTSD and CTSL1 protein expression to limit the ability of cells to use degraded material to fuel cellular metabolism and restore homeostasis. Our data highlight a new mechanism of GX15- 070-induced cell death that could be used to design novel therapeutic interventions for antiestrogen resistant breast cancer.

Original languageEnglish (US)
Pages (from-to)448-459
Number of pages12
JournalMolecular Cancer Therapeutics
Volume12
Issue number4
DOIs
StatePublished - Apr 2013

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