Pharmacological induction of cell surface GRP78 contributes to apoptosis in triple negative breast cancer cells

Abstract

Breast cancer tumor with triple-negative receptors (estrogen, progesterone and Her 2, receptors) is the most aggressive and deadly subtype, with high rates of disease recurrence and poor survival.Here, we show that induction in cell surface GRP78 by doxorubicin and tunicamycin was associated with CHOP/GADD153 upregulation and increase in apoptosis in triple negative breast cancer tumor cells.GRP78 is a major regulator of the stress induced unfolded protein response pathway and CHOP/GADD153 is a pro-apoptotic transcription factor associated exclusively with stress induced apoptosis.The blocking of cell surface GRP78 by anti-GRP78 antibody prevented apoptosis, suggesting that induction of cell surface GRP78 by doxorubicin and tunicamycin is required for apoptosis.A better understanding of stress induction of apoptotic signaling in triple negative breast cancer cells may help to define new therapeutic strategies.

Peptide Binding Glucose Regulated Protein 78 Improves Type 1 Diabetes by Preventing Pancreatic β Cell Apoptosis

“…These results coincide with previous reports in which we demonstrated that hypoxia induced a significant increase in cell surface GRP78 on endothelial cells, cardiomyocytes and neurons [10,12,13]. The re-localization and overexpression of GRP78 in the cell surface of tumor cells was also reported to be induced by ER stress produced by microenvironmental factors and chemotherapy drugs [32,33]. Moreover, STZ is known to elicit an immune and inflammatory reaction that can probably induce cell surface GRP78 expression in this model of diabetes type 1 [22].…”

“…Earlier studies demonstrated the correlation of cell surface GRP78 over expression and apoptosis in normal and cancer cells [10,[12][13][14]33]. The addition of ADoPep peptide to Ins1E cultures inhibited significantly the percent of STZ treated cells undergoing apoptosis.…”

GRP78 expression in peripheral blood mononuclear cells is a new predictive marker for the benefit of taxanes in breast cancer neoadjuvant treatment

“…Based on those and previous findings in our laboratory [26,27], we hypothesized that chemotherapy may induce ER stress not only in the tumor tissue, but also in immune cells, which affect the response to the treatment. Therefore, in this study, we focused on the ER stress response in leucocyte subpopulations exposed to neoadjuvant breast cancer treatment.…”

Caracterización del efecto de ISM1 sobre células Leucémicas Humanas

“…Estudios utilizando líneas celulares de cáncer de colon muestran que las líneas celulares HCT116 y HM7 alcanzan hasta un 85% de frecuencia de células que relocalizan GRP78 en la membrana plasmática (Hardy et al, 2012). Por otro lado, diversos estudios han demostrado que los niveles de GRP78 en la superficie celular varían dependiendo de la línea celular, por ejemplo, la línea celular MDAMB468 de cáncer de mama tiene niveles mayores de GRP78 de superficie en comparación a la línea BT474 (Raiter et al, 2014).…”

“…El análisis de citometría de flujo muestra que las células de LLA provenientes de médula ósea muestran una frecuencia media mayor de células que relocalizan GRP78 que su contraparte de sangre periférica e individuo sano, muy similar a la tendencia observada en las líneas celulares de LLA evaluadas. Las razones por las que hay una mayor frecuencia de células GRP78+ en individuos pediátricos en comparación a las líneas celulares de LLA no han sido establecidas, sin embargo, se ha demostrado que en otros modelos de cáncer, como el de mama, moléculas como la Doxorubicina o Taxotere inducen la sobreexpresión y relocalización de GRP78 hacia la membrana plasmática, incrementándose la frecuencia de células GRP78+ hasta un 50±7.7% en comparación a la frecuencia original (7%) (Raiter et al, 2014). El microambiente tumoral caracterizado por hipoxia, privación de glucosa o una alteración en la homeostasis del Ca 2+ podrían contribuir en la aparición de células leucémicas que relocalizan GRP78 en la LLA, principalmente en médula ósea.…”