Necrotic cell death: A novel outcome of BHPI-hyperactivation of the anticipatory unfolded protein response

Livezey, Mara R.

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https://hdl.handle.net/2142/102773 Copy

Description

Title

Necrotic cell death: A novel outcome of BHPI-hyperactivation of the anticipatory unfolded protein response

Author(s)

Livezey, Mara R.

Issue Date

2018-09-05

Director of Research (if dissertation) or Advisor (if thesis)

Shapiro, David J.

Doctoral Committee Chair(s)

Shapiro, David J.

Committee Member(s)

• Katzenellenbogen, Benita
• Procko, Erik
• Tajkhorshid, Emad

Department of Study

Biochemistry

Discipline

Biochemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Estrogen receptor, cancer therapy, unfolded protein response, Necrosis

Abstract

Of the roughly 1 in 8 women that develop breast cancer in their lifetimes, 70% will have estrogen receptor a positive (ERa+) cancer. The standard of care for these cancers is endocrine therapy, including aromatase inhibitors and selective estrogen receptor modulators and degraders (SERMs and SERDs), that either block the production of estrogen or competitively inhibit the binding of estrogen to ERa. These small molecule antiestrogens work by inhibiting the proproliferative actions of estrogen but after years of treatment, many cancers recur as resistant tumors. Recently, we discovered a non-competitive modulator of ERa that works in a strikingly different way. BHPI acts through ERa to hyperactivate a lethal anticipatory unfolded protein response (UPR), hijacking a normally protective and pro-proliferative action of estrogen and ERa. We have found that BHPI effectively inhibits proliferation of and kills breast cancer cells expressing constitutive and antiestrogen resistant mutations, ERaY537S and ERaD538G, that are common in metastatic breast cancer and upregulate the UPR. Surprisingly, BHPI does not kill cancer cells through classical UPR activated, CHOP-mediated, caspase-dependent apoptosis, but rather through necrosis initiated by ATP depletion. This death pathway includes rapid swelling of ERa+ cancer cells and release of arachidonic acid, and is downstream of calcium release from the endoplasmic reticulum (EnR). Interestingly, preliminary data suggests that necrotic products released from cells treated with BHPI may act as markers of inflammation that activate immune cells. Strong and sustained activation of the anticipatory UPR leading to necrotic cell death and inflammation may represent a new strategy to target ERa+ cancers.

Graduation Semester

2018-12

Type of Resource

text

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http://hdl.handle.net/2142/102773

Copyright and License Information

Copyright 2018 Mara Livezey

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