CIB1 depletion with docetaxel or TRAIL enhances triple-negative breast cancer cell death

Alexander H Chung,Marissa M Bivins,Alana L Keller,Tina M Leisner,Leslie V Parise,Gabrielle J Dardis

doi:10.1186/s12935-019-0740-2

Alexander H Chung, Marissa M Bivins + Show 4 more

Open Access

https://doi.org/10.1186/s12935-019-0740-2

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Abstract

BackgroundPatients diagnosed with triple negative breast cancer (TNBC) have limited treatment options and often suffer from resistance and toxicity due to chemotherapy. We previously found that depleting calcium and integrin-binding protein 1 (CIB1) induces cell death selectively in TNBC cells, while sparing normal cells. Therefore, we asked whether CIB1 depletion further enhances tumor-specific killing when combined with either the commonly used chemotherapeutic, docetaxel, or the cell death-inducing ligand, TRAIL.MethodsWe targeted CIB1 by RNA interference in MDA-MB-436, MDA-MB-231, MDA-MB-468, docetaxel-resistant MDA-MB-436 TNBC cells and ME16C normal breast epithelial cells alone or combination with docetaxel or TRAIL. Cell death was quantified via trypan blue exclusion using flow cytometry and cell death mechanisms were analyzed by Western blotting. Cell surface levels of TRAIL receptors were measured by flow cytometry analysis.ResultsCIB1 depletion combined with docetaxel significantly enhanced tumor-specific cell death relative to each treatment alone. The enhanced cell death strongly correlated with caspase-8 activation, a hallmark of death receptor-mediated apoptosis. The death receptor TRAIL-R2 was upregulated in response to CIB1 depletion, which sensitized TNBC cells to the ligand TRAIL, resulting in a synergistic increase in cell death. In addition to death receptor-mediated apoptosis, both combination treatments activated a non-apoptotic mechanism, called paraptosis. Interestingly, these combination treatments also induced nearly complete death of docetaxel-resistant MDA-MB-436 cells, again via apoptosis and paraptosis. In contrast, neither combination treatment induced cell death in normal ME16C cells.ConclusionNovel combinations of CIB1 depletion with docetaxel or TRAIL selectively enhance naive and docetaxel-resistant TNBC cell death while sparing normal cell. Therefore, combination therapies that target CIB1 could prove to be a safe and durable strategy for treatment of TNBC and potentially other cancers.

Highlights

Patients diagnosed with triple negative breast cancer (TNBC) have limited treatment options and often suffer from resistance and toxicity due to chemotherapy
We found that calcium and integrinbinding protein 1 (CIB1) depletion enhanced docetaxel-induced cell death selectively in TNBC over normal cells largely via a death receptor-mediated, as opposed to mitochondrial-mediated apoptosis
CIB1 depletion selectively enhances docetaxel‐induced TNBC cell death We previously reported that CIB1 depletion leads to TNBC cell death while sparing normal cells [8], suggesting that CIB1 may be a viable, safe target

Summary

Introduction

Patients diagnosed with triple negative breast cancer (TNBC) have limited treatment options and often suffer from resistance and toxicity due to chemotherapy. We asked whether CIB1 depletion further enhances tumor-specific killing when combined with either the commonly used chemotherapeutic, docetaxel, or the cell death-inducing ligand, TRAIL. 15–20% of all breast cancer deaths in the U.S occur in patients diagnosed with triple-negative breast cancer (TNBC), a subtype defined by a lack of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 In clinical trials that targeted the epidermal growth factor receptor (EGFR), which is commonly upregulated/activated in TNBC, there was no improvement in chemotherapeutic efficacy [5,6,7]. While ongoing clinical trials are testing PI3K–AKT and MEK–ERK signaling pathways downstream of EGFR, toxicity remains unresolved with a modest to no increase in patient survival (NCT02423603, NCT01964924)

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