Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover

Fitzwalter, Brent E.; Towers, Christina G.; Sullivan, Kelly D.; Andrysík, Zdeněk; Hoh, Maria; Ludwig, Michael P.; O’Prey, Jim; Ryan, Kevin M.; Espinosa, Joaquín M.; Morgan, Michael J.; Thorburn, Andrew

doi:10.1016/j.devcel.2018.02.014

Cited by 170 publications

(145 citation statements)

References 25 publications

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“…Cancer is frequently a result of disrupted coordination between the suppressive signals from internal or external stresses and the stimulating signals from growth factors and nutrients (34). The mTOR signaling is a key regulator involved in many facets of carcinogenic and metabolic events, including autophagy, apoptosis (35)(36)(37)(38)(39)(40)(41), migration and invasion (42), differentiation, energy metabolism, and inflammation (43). Autophagy is a stress-responsive catabolic process followed by lysosomal degradation of intracellular components (44), removing aggregated protein, damaged organelles, and pathogen clearance, in order to provide energy for normal cellular function.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

et al. 2019

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Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS.NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer-specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC.Significance: Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

et al. 2019

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“…Recent studies have shown that the aberrant regulation of apoptosis results in uncontrolled cell proliferation . As PLAC8 overexpression facilitates BC cell proliferation, we assessed whether increased or decreased PLAC8 expression contributes to cell apoptosis to influence BC progression.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have shown that the aberrant regulation of apoptosis results in uncontrolled cell proliferation. [20][21][22] As PLAC8 overexpression facilitates BC cell proliferation, we assessed whether increased or decreased PLAC8 expression contributes to cell apoptosis to influence BC progression. The results revealed that PLAC8transfected T47D cells were inhibited for apoptosis, whereas PLAC8 knockdown significantly induced apoptosis in Bcap-37 cells ( Figure 4A,B).…”

Section: Plac8 Silencing Induces Caspase 3/9 Activation Bcl-2 Up-rmentioning

confidence: 99%

PLCA8 suppresses breast cancer apoptosis by activating the PI3k/AKT/NF‐κB pathway

Mao

Chen

Jia

et al. 2019

J Cellular Molecular Medi

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The cysteine‐rich lysosomal protein placenta‐specific 8 (PLAC8), also called onzin, has been shown to be involved in many types of cancers, and its role is highly dependent on cellular and physiological contexts. However, the precise function of PLAC8 in breast cancer (BC) progression remains unclear. In this study, we investigated both the clinical significance and biological functions of PLAC8 in BC progression. First, high PLAC8 expression was observed in primary BC tissues compared with adjacent normal tissues through immunohistochemistry analysis. The results of in vitro and in vivo assays further confirmed that PLAC8 overexpression promotes cell proliferation and suppress BC cell apoptosis, whereas PLAC8 silencing has the opposite effect. In addition, the forced expression of PLAC8 greatly induces cell migration, partially by affecting the EMT‐related genes, including down‐regulating E‐cadherin expression and facilitating vimentin expression. Further mechanistic analysis confirmed that PLAC8 contributes to cell proliferation and suppresses cell apoptosis in BC by activating the PI3K/AKT/NF‐κB pathway. The results of our study provide new insights into an oncogenic role of PLAC8 and reveal a novel PLAC8/ PI3K/AKT/NF‐κB pathway as a potential therapeutic target for BC.

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“…Interestingly, recent work from Thorburn et al . shows that autophagy can regulate apoptosis by degrading cytoplasmic FOXO3A . Therefore, these results regarding the link between autophagy, FOXO3A and the maintenance of LSCs warrant further investigation.…”

Section: Role and Regulation Of Autophagy In CML And Lscsmentioning

confidence: 85%

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

2018

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Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR-ABL-independent mechanism(s).

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Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover

Cited by 170 publications

References 25 publications

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

PLCA8 suppresses breast cancer apoptosis by activating the PI3k/AKT/NF‐κB pathway

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

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