Inhibition of GATE-16 attenuates ATRA-induced neutrophil differentiation of APL cells and interferes with autophagosome formation

Brigger, Daniel; Torbett, Bruce E.; Chen, Joy; Fey, Martin F.; Tschan, Mario P.

doi:10.1016/j.bbrc.2013.07.056

Cited by 28 publications

(26 citation statements)

References 42 publications

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“…We then evaluated the effect of FASN expression on the transcription of the following TFEB target genes: BECN1, GABARAP, STK4 and WDR45. All 4 TFEB targets showed increased expression upon ATRA treatment, in line with previous studies (Orfali et al, 2015;Brigger et al, 2013Brigger et al, , 2014a) ( Figure 5I). Knock down of FASN led to a further increase in the expression of 3/4 TFEB targets analyzed ( Figure 5I).…”

Section: Fasn Expression Negatively Affects Transcription Factor Eb (supporting

confidence: 91%

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Humbert

Seiler

Mosimann

et al. 2020

Preprint

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Switzerland 2 TRANSAUTOPHAGY: European network for multidisciplinary research and translation of autophagy knowledge, COST Action CA15138 Abstract Acute myeloid leukemia (AML) is a blood cancer characterized by a block in differentiation and increased survival of the resulting AML blast cells. While standard chemotherapy for AML cures only 30% of patients, differentiation-inducing therapy using all-trans retinoic acid (ATRA) in combination with arsenic trioxide achieves 90% cure rates in acute promyelocytic leukemia (APL). A better understanding of the molecular mechanisms underlying ATRA therapy in APL may provide new perspectives in the treatment of additional AML subtypes.Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis. While FASN levels are very low in healthy adult tissues, it is often highly expressed in cancer cells, thus representing a potential therapeutic target. We found that FASN mRNA levels were significantly higher in AML patients than in healthy granulocytes or CD34 + hematopoietic progenitors in two AML cohorts (n=68, n=203) (p<0.05). Accordingly, FASN levels decreased during ATRA-mediated granulocytic differentiation of APL cells, partially via autophagic degradation. Furthermore, our data suggests that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG), accelerates the differentiation of APL cell lines and significantly resensitized ATRA refractory non-APL AML cells. Decreasing FASN expression reduced mTOR activity and promoted translocation of transcription factor EB (TFEB) to the nucleus. Lysosomal biogenesis was activated, consistent with TFEB transcriptional activation of CLEAR network genes.Together, our data demonstrates that inhibiting FASN expression in combination with ATRA treatment promotes granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells. BioRXiv

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Section: Fasn Expression Negatively Affects Transcription Factor Eb (supporting

confidence: 91%

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Humbert

Seiler

Mosimann

et al. 2020

Preprint

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“…Within the hematopoietic system, the importance of ATG7 has been demonstrated in normal hematopoietic stem cell renewal, quiescence and remodeling, while also being involved in the differentiation of erythrocytes, lymphocytes and mast cells [13]. The importance of other autophagy regulators such as ULK1, ATG5, PI3KC3, SQSTM1 [20], BECN1 [19], DRAM-1 [31] and GATE-16 [21] for APL cell differentiation has been evaluated; however, the effect of ATG7 knockdown has not previously been examined. Our study thus establishes a novel and important role for ATG7 in APL differentiation and by inference, response to differentiation therapy.…”

Section: Discussionmentioning

confidence: 99%

Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation

Orfali

O’Donovan

Nyhan

et al. 2015

Experimental Hematology

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Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has only achieved success in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In this study we demonstrate the functional importance of autophagy in APL cell differentiation. We show that autophagy is increased during ATRA-induced granulocytic differentiation of the APL cell line NB4, and that this is associated with increased expression of LC3-II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin (sh)RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we show that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML.

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“…Importantly, ATRA-induced differentiation of the APL cell line, NB4, involves induction of macroautophagy. 9 , 10 , 11 , 12 In addition to its cytodifferentiating capacity in APL, ATRA has been proposed as an antitumorigenic agent for other types of cancer. The antiproliferative, cytodifferentiating and proapoptotic effects of retinoids are predominantly mediated by the nuclear hormone retinoid acid receptors RAR α , RAR β and RAR γ.…”

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confidence: 99%

Activation of RARα induces autophagy in SKBR3 breast cancer cells and depletion of key autophagy genes enhances ATRA toxicity

et al. 2015

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All-trans retinoic acid (ATRA), a pan-retinoic acid receptor (RAR) agonist, is, along with other retinoids, a promising therapeutic agent for the treatment of a variety of solid tumors. On the one hand, preclinical studies have shown promising anticancer effects of ATRA in breast cancer; on the other hand, resistances occurred. Autophagy is a cellular recycling process that allows the degradation of bulk cellular contents. Tumor cells may take advantage of autophagy to cope with stress caused by anticancer drugs. We therefore wondered if autophagy is activated by ATRA in mammary tumor cells and if modulation of autophagy might be a potential novel treatment strategy. Indeed, ATRA induces autophagic flux in ATRA-sensitive but not in ATRA-resistant human breast cancer cells. Moreover, using different RAR agonists as well as RARα-knockdown breast cancer cells, we demonstrate that autophagy is dependent on RARα activation. Interestingly, inhibition of autophagy in breast cancer cells by either genetic or pharmacological approaches resulted in significantly increased apoptosis under ATRA treatment and attenuated epithelial differentiation. In summary, our findings demonstrate that ATRA-induced autophagy is mediated by RARα in breast cancer cells. Furthermore, inhibition of autophagy results in enhanced apoptosis. This points to a potential novel treatment strategy for a selected group of breast cancer patients where ATRA and autophagy inhibitors are applied simultaneously.

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Inhibition of GATE-16 attenuates ATRA-induced neutrophil differentiation of APL cells and interferes with autophagosome formation

Cited by 28 publications

References 42 publications

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation

Activation of RARα induces autophagy in SKBR3 breast cancer cells and depletion of key autophagy genes enhances ATRA toxicity

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