Targeting mdr1 and endocrine therapy-­resistant cancers through estrogen receptor

Estrogens, acting via estrogen receptor (ER), stimulate cell proliferation and are associated with the development of aggressive breast and ovarian cancers. Endoplasmic reticulum (EnR) stress signaling cascade, the unfolded protein response (UPR), has documented in various human cancers and diseases. However, the precise roles of UPR signaling in development of hormone-dependent gynecological cancers were unknown. Here we show that the activation of UPR prior to EnR stress, also known as the anticipatory UPR activation, is a new paradigm for estrogen-ER action. We found that 17-estradiol (E2), acting through ER, rapidly activates Phospholipase C (PLC) leading to the production of inositol triphosphate (IP3). The IP3 binds to and opens endoplasmic reticulum (EnR) IP3 receptors (IP3R) leading to extremely rapid (<1 min.) efflux of calcium (Ca2+) from the lumen of the EnR into the cell body. Elevated intracellular Ca2+ primes cells for subsequent actions of E2-ER; depletion of EnR Ca2+ activates the unfolded protein response (UPR), inducing the important chaperone BiP/GRP78 (glucose-regulated protein 78 kDa). Activation of this pathway is required for E2-ER-regulated gene expression, cell proliferation and protects cells against stress. We target this pathway with our medically promising ER biomodulator, BHPI, which uses the same pathway as E2, but induces toxic hyperactivation of the anticipatory UPR, shifting it from protective to cytotoxic. As a result, at nanomolar concentration, BHPI blocked growth and often killed diverse therapy-resistant and ER-positive breast, ovarian, and endometrial cancer cells. Moreover, in a mouse xenograft, BHPI treatment resulted in rapid and substantial regression of pre-existing tumors. Extending the novel action of BHPI by hyperactivating anticipatory UPR, a new approach to inactivating multidrug resistance protein 1 (MDR1) in therapy resistant breast and ovarian cancer cells was developed. To evaluate the effectiveness of BHPI in reversing multidrug resistance in vivo, multidrug resistant OVCAR-3 ovarian cells, that are resistant to all known anticancer agents, were used in an orthotopic mouse tumor model. This study demonstrated that BHPI in combination with the taxane, paclitaxel, reduced ovarian tumor burden and the circulating tumor antigen, CA125, to undetectable levels. Taken together, these studies demonstrate the importance of cross-talk between steroid hormone action and the anticipatory UPR pathway in the development of hormone-dependent cancer. We show that targeting anticipatory UPR signaling is a promising new way to attack therapy-resistant cancers. Moreover, estrogens are known to have significant effects in neurodegenerative diseases, metabolic syndrome, and diabetes. Our studies of the anticipatory UPR pathway stimulated by steroid hormones in cancer cells open the way for further studies of the role of the estrogen-activated anticipatory UPR pathway in the pathology of these diverse disease states.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2017

Author dc:creator

• Zheng, Xiaobin

Contributors dc:contributor

• Shapiro, David J.
• Fratti, Rutilio A.
• Nelson, Erik R.
• Zhang, Kai

• MDR1
• Estrogen Receptor
• Unfolded protein response (UPR)
• ATP

Statement dc:rights

• Copyright 2016 Xiaobin Zheng

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/95284

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/95284