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1.
Oncotarget ; 9(51): 29698-29714, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-30038714

RESUMO

In many cancers, combination therapy regimens are successfully improving response and survival rates, but the challenges of toxicity remain. GRP78, the master regulator of the unfolded protein response, is emerging as a target that is upregulated in tumors, specifically following treatment, and one that impacts tumor cell survival and disease recurrence. Here, we show IT-139, an antitumor small molecule inhibitor, suppresses induction of GRP78 from different types of endoplasmic reticulum (ER) stress in a variety of cancer cell lines, including those that have acquired therapeutic resistance, but not in the non-cancer cells being tested. We further determined that IT-139 treatment exacerbates ER stress while at the same time suppresses GRP78 induction at the transcriptional level. Our studies revealed a differential effect of IT-139 on chaperone protein family expression at multiple levels in different cancer cell lines. In xenograft studies, IT-139 decreased BRAF inhibitor upregulation of GRP78 expression in the tumor, while having minimal effect on GRP78 expression in the adjacent normal cells. The preferential decrease in GRP78 levels in tumor cells over normal cells, supported by the manageable safety profile seen in the Phase 1 clinical trial, reinforce the value IT-139 brings to combination therapies as it continues its clinical development.

2.
Mol Cell Oncol ; 4(6): e1345350, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29209644

RESUMO

Metaplasia is emerging as a key process in tumorigenesis. We discovered that 2 essential endoplasmic reticulum (ER) chaperones, 78-kilodalton glucose-regulated protein (GRP78) and 94-kilodalton glucose-regulated protein (GRP94) have a role in metaplasia. Grp78 haploinsufficiency in the mouse pancreas impairs acinar-to-ductal metaplasia, whereas in the uterus, Grp94 loss induces squamous cell metaplasia; both resulting in tumor suppression.

3.
Proc Natl Acad Sci U S A ; 114(20): E4020-E4029, 2017 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-28461470

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;KrasG12D/+;p53f/+ (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a Grp78f/+ allele (PKC78f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of Grp78 (c78f/+ ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78f/+ and c78f/+ pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.


Assuntos
Carcinoma Ductal Pancreático/genética , Transdiferenciação Celular , Proteínas de Choque Térmico/genética , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Células Acinares/metabolismo , Animais , Carcinogênese , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Chaperona BiP do Retículo Endoplasmático , Feminino , Haploinsuficiência , Proteínas de Choque Térmico/metabolismo , Masculino , Metaplasia , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fator de Crescimento Transformador alfa/metabolismo
4.
Sci Rep ; 7: 40919, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28145503

RESUMO

GRP78, a multifunctional protein with potent cytoprotective properties, is an emerging therapeutic target to combat cancer development, progression and drug resistance. The biological consequences of prolonged reduction in expression of this essential chaperone which so far has been studied primarily in young mice, was investigated in older mice, as older individuals are likely to be important recipients of anti-GRP78 therapy. We followed cohorts of Grp78+/+ and Grp78+/- male and female mice up to 2 years of age in three different genetic backgrounds and characterized them with respect to body weight, organ integrity, behavioral and memory performance, cancer, inflammation and chemotoxic response. Our results reveal that body weight, organ development and integrity were not impaired in aged Grp78+/- mice. No significant effect on cancer incidence and inflammation was observed in aging mice. Interestingly, our studies detected some subtle differential trends between the WT and Grp78+/- mice in some test parameters dependent on gender and genetic background. Our studies provide the first evidence that GRP78 haploinsufficiency for up to 2 years of age has no major deleterious effect in rodents of different genetic background, supporting the merit of anti-GRP78 drugs in treatment of cancer and other diseases affecting the elderly.


Assuntos
Envelhecimento/genética , Antineoplásicos/toxicidade , Comportamento Animal , Haploinsuficiência , Proteínas de Choque Térmico/genética , Homeostase , Neoplasias/genética , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Peso Corporal , Distúrbios Induzidos Quimicamente/genética , Chaperona BiP do Retículo Endoplasmático , Feminino , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL
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