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Aberrant NFATc1 signaling counteracts TGF?-mediated growth arrest and apoptosis induction in pancreatic cancer progression.

ABSTRACT: Given its aggressive tumor biology and its exceptional therapy resistance, pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <8%. At the cellular level, PDAC is largely driven by the activation of signaling pathways that eventually converge in altered, tumor-promoting transcription programs. In this study, we sought to determine the interplay between transforming growth factor ? (TGF?) signaling and activation of the inflammatory transcription factor nuclear factor of activated T cells (NFATc1) in the regulation of transcriptional programs throughout PDAC progression. Genome-wide transcriptome analysis and functional studies performed in primary PDAC cells and transgenic mice linked nuclear NFATc1 expression with pro-proliferative and anti-apoptotic gene signatures. Consistently, NFATc1 depletion resulted in downregulation of target genes associated with poor PDAC outcome and delayed pancreatic carcinogenesis in vivo. In contrast to previous reports and consistent with a concept of retained tumor suppressive TGF? activity, even in established PDAC, TGF? treatment reduced PDAC cell proliferation and promoted apoptosis even in the presence of oncogenic NFATc1. However, combined TGF? treatment and NFATc1 depletion resulted in a tremendous abrogation of tumor-promoting gene signatures and functions. Chromatin studies implied that TGF?-dependent regulators compete with NFATc1 for the transcriptional control of jointly regulated target genes associated with an unfavorable PDAC prognosis. Together, our findings suggest opposing consequences of TGF? and NFATc1 activity in the regulation of pro-tumorigenic transcription programs in PDAC and emphasize the strong context-dependency of key transcription programs in the progression of this devastating disease.

SUBMITTER: Hasselluhn MC

PROVIDER: S-EPMC6554303 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Aberrant NFATc1 signaling counteracts TGFβ-mediated growth arrest and apoptosis induction in pancreatic cancer progression.

Hasselluhn Marie C MC Schmidt Geske E GE Ellenrieder Volker V Johnsen Steven A SA Hessmann Elisabeth E

Cell death & disease 20190606 6

Given its aggressive tumor biology and its exceptional therapy resistance, pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <8%. At the cellular level, PDAC is largely driven by the activation of signaling pathways that eventually converge in altered, tumor-promoting transcription programs. In this study, we sought to determine the interplay between transforming growth factor β (TGFβ) signaling and activation o ...[more]

PMID: 31171768

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Project description:In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the 'quasisynaptical' feeding of calcium to the mitochondria to promote oxidative phosphorylation. However, persistent Ca2+ release results in mitochondrial Ca2+ overload and consequent apoptosis. Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca2+-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca2+ influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knock-in clones display increased cytosolic Ca2+ release from the endoplasmic reticulum and sensitization to Ca2+-dependent apoptotic stimuli. The phosphatase and tensin homologue (PTEN) gene is frequently mutated or lost in human tumours and syndromes that predispose individuals to cancer. We found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten-/- mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wild-type PTEN or a catalytically dead mutant stabilizes IP3R3 and induces persistent Ca2+ mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlate in human prostate cancer. Both in cell culture and xenograft models, a non-degradable IP3R3 mutant sensitizes tumour cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca2+-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitizes xenotransplanted tumours to photodynamic therapy. In summary, we identify a novel molecular mechanism that limits mitochondrial Ca2+ overload to prevent cell death. Notably, we provide proof-of-principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.

Dataset Information

Aberrant NFATc1 signaling counteracts TGF?-mediated growth arrest and apoptosis induction in pancreatic cancer progression.

Publications

Aberrant NFATc1 signaling counteracts TGFβ-mediated growth arrest and apoptosis induction in pancreatic cancer progression.

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