FATE 1 antagonizes calcium‐ and drug‐induced apoptosis by uncoupling ER and mitochondria

Abstract

Several stimuli induce programmed cell death by increasing Ca 2+transfer from the endoplasmic reticulum (ER) to mitochondria. Perturbation of this process has a special relevance in pathologies as cancer and neurodegenerative disorders. Mitochondrial Ca 2+ uptake mainly takes place in correspondence of mitochondria-associated ER membranes (MAM), specialized contact sites between the two organelles. Here, we show the important role of FATE1, a cancer-testis antigen, in the regulation of ER-mitochondria distance and Ca 2+ uptake by mitochondria.FATE1 is localized at the interface between ER and mitochondria, fractionating into MAM. FATE1 expression in adrenocortical carcinoma (ACC) cells under the control of the transcription factor SF-1 decreases ER-mitochondria contact and mitochondrial Ca 2+ uptake, while its knockdown has an opposite effect. FATE1 also decreases sensitivity to mitochondrial Ca 2+-dependent proapoptotic stimuli and to the chemotherapeutic drug mitotane. In patients with ACC, FATE1 expression in their tumor is inversely correlated with their overall survival. These results show that the ER-mitochondria uncoupling activity of FATE1 is harnessed by cancer cells to escape apoptotic death and resist the action of chemotherapeutic drugs.

Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

“…For example, FATE1, a cancer-testis antigen localized at MAM, was recently implicated in the regulation of Ca 2+ -and drugdependent apoptosis in cancer cells by modulating ERmitochondria distance. Therefore, high FATE1 expression in the tumor is a poor prognosis indicator in patients with adrenocortical carcinoma (Doghman-Bouguerra et al 2016). Furthermore, the ER-localized thioredoxin-related transmembrane protein 1 (TMX1) was shown to interact with SERCA2b under oxidizing conditions in a thioldependent manner to decrease SERCA activity and, thus, the ER Ca 2+ load.…”

The next step: mechanisms driving adrenocortical carcinoma metastasis

“…In mouse models, constitutive adrenocortical beta-catenin activation, obtained using different transgenic strategies, leads to tumorigenesis (Berthon et al 2010, Heaton et al 2012); • high expression of the G1 cyclin E, which is involved in cell proliferation, is associated with shorter DFS (Tissier et al 2004); • high levels of excision repair cross-complementing group 1 (ERCC1) protein, involved in nucleotide excision repair of DNA, correlate with reduced OS selectively in ACC patients who received platinumbased chemotherapy (Ronchi et al 2009); • FATE1 is a cancer-testis antigen localized at the interface between the endoplasmic reticulum and mitochondria that modulates calcium-mediated apoptosis in adrenocortical cells. High FATE1 levels are associated with reduced OS (Doghman-Bouguerra et al 2016); • high expression of the glucose transporter GLUT1 is associated with reduced OS (Fenske et al 2009, Pinheiro et al 2015 and reduced DFS (Pinheiro et al 2015). In the latter study, high levels of the monocarboxylate transporter (MCT) MCT1, which allows lactate to enter the cell, and the pH regulator carbonic anhydrase IX (CAIX) were also associated with shorter OS, while a high expression of MCT2, which pumps lactate outside the cell, was associated with increased OS.…”

“…In ACT cells, SF-1 regulates different sets of target genes according to its dosage (Doghman et al 2007a(Doghman et al , 2013. Some of these dosage-dependent SF-1 target genes have a direct role in decreasing apoptotic death (NOV, FATE1; Doghman et al 2007b, Doghman-Bouguerra et al 2016 and increasing invasion of tumor cells (VAV2; Ruggiero et al 2017). VAV2 is a guanine nucleotide exchange factor regulating cytoskeleton remodelling (Fig.…”

Biochemical mechanism of the o,p’-DDD effect on the adrenal cortex

“…FATE1 is expressed in adrenal cancer cells under the control of the transcription factor SF1 and increases the distance between ER and mitochondria, reducing mitochondrial Ca 2+ uptake. FATE1 also decreases sensitivity to proapoptoticeffectsandtoo,p'-DDD [34].…”

“…Thus, MAMs may be considered as functional adapters of changes in cell homeostasis. It was shown in [34] that FATE1, a cancer-testis antigen, plays an important role in the regulation of the ER -mitochondria distance [34]. FATE1 is expressed in adrenal cancer cells under the control of the transcription factor SF1 and increases the distance between ER and mitochondria, reducing mitochondrial Ca 2+ uptake.…”