Deregulated FADD expression and phosphorylation in T-cell lymphoblastic lymphoma

Marín-Rubio, José Luis; Arriba, M.; Cobos-Fernández, María Ángeles; González-Sánchez, Laura; Ors, Inmaculada; Sastre, Isabel; Fernández‐Piqueras, José; Villa‐Morales, María

doi:10.18632/oncotarget.11370

Cited by 9 publications

(20 citation statements)

References 44 publications

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“…In addition to its functions in apoptosis, FADD can also induce cell survival, cell cycle progression, and cell proliferation, depending on its phosphorylation and cellular localization [97]. Disrupted FADD phosphorylation has been inversely correlated with tumor aggressiveness in T-cell lymphoblastic lymphomas [98]. Moreover, decreased FADD is associated with cognitive impairment and clinical dementia in the elderly [99].…”

Section: Extrinsic Pathwaymentioning

confidence: 99%

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

Cavalcante

Schaan

Cabral

et al. 2019

IJMS

162

112

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Apoptosis is one of the main types of regulated cell death, a complex process that can be triggered by external or internal stimuli, which activate the extrinsic or the intrinsic pathway, respectively. Among various factors involved in apoptosis, several genes and their interactive networks are crucial regulators of the outcomes of each apoptotic phase. Furthermore, mitochondria are key players in determining the way by which cells will react to internal stress stimuli, thus being the main contributor of the intrinsic pathway, in addition to providing energy for the whole process. Other factors that have been reported as important players of this intricate molecular network are miRNAs, which regulate the genes involved in the apoptotic process. Imbalance in any of these mechanisms can lead to the development of several illnesses, hence, an overall understanding of these processes is essential for the comprehension of such situations. Although apoptosis has been widely studied, the current literature lacks an updated and more general overview on this subject. Therefore, here, we review and discuss the mechanisms of apoptosis, highlighting the roles of genes, miRNAs, and mitochondria involved in this type of cell death.

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Section: Extrinsic Pathwaymentioning

confidence: 99%

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

Cavalcante

Schaan

Cabral

et al. 2019

IJMS

162

112

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“…FADD expression is altered in many cancer types. This is, however, a controversial issue, since both overexpression [4,5,6,7,8,9,10] and downregulation [11,12,13,14,15] have been observed, depending on the cancer type. According to The Human Protein Atlas, FADD protein levels are low in most normal tissues.…”

Section: Regulation Of Fadd Gene Expressionmentioning

confidence: 99%

“…In NSCLC, four missense mutations of FADD were detected in 80 samples (5%) [50], whereas only one FADD mutation was found in 98 colorectal adenocarcinomas (1%) and no FADD mutation was detected in 116 advanced gastric adenocarcinomas [51]. Moreover, no mutations in FADD were found either in 92 samples from diverse hematological malignancies [52], in 24 lung adenocarcinomas with high FADD expression [5], in 15 osteosarcoma tumor samples [53], or in murine (14 samples) [12] and human (22 samples) [13] T-cell lymphoblastic lymphoma (T-LBL).…”

Section: Regulation Of Fadd Gene Expressionmentioning

confidence: 99%

“…FADD can recruit proteins that regulate the NF-κB and MAPK pathways, which promote proliferation and cell cycle progression [5]. Our group has reported a reduction of FADD together with reduced apoptosis in T-LBL samples, but the accumulation of phosphorylated FADD in the nuclei of tumor cells [12,13]. Interestingly, we found that levels of phosphorylated FADD correlated with the proliferation capacity of tumor cells, supporting previous evidence in different cancer types [5,102].…”

Section: The Roles Of Fadd and Their Participation In Cancermentioning

confidence: 99%

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FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications

Marín-Rubio

Vela‐Martín

Fernández‐Piqueras

et al. 2019

Cancers

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FADD was initially described as an adaptor molecule for death receptor-mediated apoptosis, but subsequently it has been implicated in nonapoptotic cellular processes such as proliferation and cell cycle control. During the last decade, FADD has been shown to play a pivotal role in most of the signalosome complexes, such as the necroptosome and the inflammasome. Interestingly, various mechanisms involved in regulating FADD functions have been identified, essentially posttranslational modifications and secretion. All these aspects have been thoroughly addressed in previous reviews. However, FADD implication in cancer is complex, due to pleiotropic effects. It has been reported either as anti- or protumorigenic, depending on the cell type. Regulation of FADD expression in cancer is a complex issue since both overexpression and downregulation have been reported, but the mechanisms underlying such alterations have not been fully unveiled. Posttranslational modifications also constitute a relevant mechanism controlling FADD levels and functions in tumor cells. In this review, we aim to provide detailed, updated information on alterations leading to changes in FADD expression and function in cancer. The participation of FADD in various biological processes is recapitulated, with a mention of interesting novel functions recently proposed for FADD, such as regulation of gene expression and control of metabolic pathways. Finally, we gather all the available evidence regarding the clinical implications of FADD alterations in cancer, especially as it has been proposed as a potential biomarker with prognostic value.

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“…Mechanistically, FADD bridges the activated death receptor and the initiator caspases to augment cell death signaling [ 3 , 6 ]. However, in the majority of cancer cells, the cytosolic expression of FADD is typically suppressed [ 9 , 15 , 53 , 54 , 55 ]. This impediment is likely because of post-translational modifications (PTMs) and nuclear localization of FADD [ 9 , 10 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

Cell-Penetrable Peptide-Conjugated FADD Induces Apoptosis and Regulates Inflammatory Signaling in Cancer Cells

Ranjan

Waghela

Vaidya

et al. 2020

IJMS

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Dysregulated expression of Fas-associated death domain (FADD) is associated with the impediment of various cellular pathways, including apoptosis and inflammation. The adequate cytosolic expression of FADD is critical to the regulation of cancer cell proliferation. Importantly, cancer cells devise mechanisms to suppress FADD expression and, in turn, escape from apoptosis signaling. Formulating strategies, for direct delivery of FADD proteins into cancer cells in a controlled manner, may represent a promising therapeutic approach in cancer therapy. We chemically conjugated purified FADD protein with cell permeable TAT (transactivator of transcription) peptide, to deliver in cancer cells. TAT-conjugated FADD protein internalized through the caveolar pathway of endocytosis and retained in the cytosol to augment cell death. Inside cancer cells, TAT-FADD rapidly constituted DISC (death inducing signaling complex) assembly, which in turn, instigate apoptosis signaling. The apoptotic competency of TAT-FADD showed comparable outcomes with the conventional apoptosis inducers. Notably, TAT-FADD mitigates constitutive NF-κB activation and associated downstream anti-apoptotic genes Bcl2, cFLIPL, RIP1, and cIAP2, independent of pro-cancerous TNF-α priming. In cancer cells, TAT-FADD suppresses the canonical NLRP3 inflammasome priming and restricts the processing and secretion of proinflammatory IL-1β. Our results demonstrate that TAT-mediated intracellular delivery of FADD protein can potentially recite apoptosis signaling with simultaneous regulation of anti-apoptotic and proinflammatory NF-κB signaling activation in cancer cells.

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Deregulated FADD expression and phosphorylation in T-cell lymphoblastic lymphoma

Cited by 9 publications

References 44 publications

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications

Cell-Penetrable Peptide-Conjugated FADD Induces Apoptosis and Regulates Inflammatory Signaling in Cancer Cells

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