Targeting the ATF4 pathway in cancer therapy

Singleton, Dean; Harris, Adrian L.

doi:10.1517/14728222.2012.728207

Cited by 119 publications

(117 citation statements)

References 86 publications

(73 reference statements)

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“…Both Nrf2 and ATF4 play crucial roles in cancer cell survival and growth (36,(56)(57)(58)(59). Nrf2 activates the antioxidative pathway by inducing a variety of antioxidant proteins in addition to xCT.…”

Section: Discussionmentioning

confidence: 99%

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Mimura

Okada

et al. 2014

Molecular and Cellular Biology

165

153

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The ubiquitin-proteasome pathway degrades ubiquitinated proteins to remove damaged or misfolded protein and thus plays an important role in the maintenance of many important cellular processes. Because the pathway is also crucial for tumor cell growth and survival, proteasome inhibition by specific inhibitors exhibits potent antitumor effects in many cancer cells. xCT, a subunit of the cystine antiporter system x c ؊ , plays an important role in cellular cysteine and glutathione homeostasis. Several recent reports have revealed that xCT is involved in cancer cell survival; however, it was unknown whether xCT affects the cytotoxic effects of proteasome inhibitors. In this study, we found that two stress-inducible transcription factors, Nrf2 and ATF4, were upregulated by proteasome inhibition and cooperatively enhance human xCT gene expression upon proteasome inhibition. In addition, we demonstrated that the knockdown of xCT by small interfering RNA (siRNA) or pharmacological inhibition of xCT by sulfasalazine (SASP) or (S)-4-carboxyphenylglycine (CPG) significantly increased the sensitivity of T24 cells to proteasome inhibition. These results suggest that the simultaneous inhibition of both the proteasome and xCT could have therapeutic benefits in the treatment of bladder tumors.

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Section: Discussionmentioning

confidence: 99%

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Mimura

Okada

et al. 2014

Molecular and Cellular Biology

165

153

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“…This translational reprogramming is exploited by tumor cells to enhance their protection against stress [22,29,30]. One key mRNA which undergoes selective translation is ATF4, a ER stressinduced transcription factor that activates transcription of downstream stress-response genes such as CHOP, components of the endoplasmicreticulum-associated protein degradation (ERAD) machinery, and molecular chaperones [14,31]. Translational inhibition due to eIF2α phosphorylation leads to selective translation of ATF4, therefore reprogramming gene expression under stress.…”

Section: Selective Translation Mechanisms Under Cell Stressmentioning

confidence: 99%

“…Transcripts possessing uORF in their 5′UTRs, such as ATF4, CHOP and GADD34 components of the UPR and ER stress response [27,37], are translationally induced under hypoxia in both tumor and normal cells, which is dependent on eIF2α phosphorylation [36,60,62,91]. More specifically, ATF4, which is a transcription factor acting as a major downstream mediator of the PERK-eIF2α axis (for review [31]), is critical for supporting cell survival under hypoxia and for promoting tumor growth. Indeed, targeted inhibition of ATF4 severely compromises survival of both tumor and normal cells under hypoxia [29,71,92], and prevents growth of tumor xenografts [93].…”

Section: Uorfsmentioning

confidence: 99%

Stress-mediated translational control in cancer cells

Leprivier

Rotblat

Khan

et al. 2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

110

112

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“…Previous studies have demonstrated that ATF4 is involved in oncogenic process. For example, Horiguchi et al reported that ATF4 promoted oncogene-induced neoplastic transformation by suppressing the expression of the cellular senescence-associated genes INK4a and ARF [6, 7]. ATF4 over-expressing cell lines were used to show that ATF4 increased drug resistance to cisplatin, doxorubicin, etoposide, SN-38 and vincristine [8].…”

Section: Introductionmentioning

confidence: 99%

Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation

Zong

Feng

Cheng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Activating transcription factor 4 (ATF4) is a member of the activating transcription factor family which regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses. ATF4 is also over-expressed in human solid tumors, although its effect on responsiveness to radiation is largely unexplored. Methods: Real-time PCR was used to detect ATF4 mRNA levels in cells treated with different doses of ⁶⁰Coγ radiation. Cell viability was assayed using a cell counting kit. The cell cycle was analyzed using flow cytometry, and cell apoptosis was assayed using Annexin V-PI double labeling. Small interfering RNA (siRNA) against ATF4 was transfected into ECV304 cells using Lipofectamine 2000. An ATF4 over-expression plasmid (p-ATF4-CGN) was transfected into HEK293 cells that endogenously expressed low levels of ATF4. The levels of intracellular reactive oxygen species (ROS) were measured using CM-H2DCFDA as a probe. Results: ATF4 mRNA and protein expression levels were higher after radiation and increased in a dose- and time-dependent manner in AHH1 lymphoblast cells (P < 0.05). An increase in ATF4 levels was also observed after radiation in primary murine spleen cells, human endothelial ECV304 cells, human liver LO2 cells, breast cancer MCF7 cells, and human hepatocellular carcinoma HEPG2 cells. No change was observed in human embryonic kidney 293 (HEK293) cells. Over-expressing ATF4 in HEK293 cells inhibited cell proliferation, increased cell apoptosis and significantly increased the proportion of cells in G1 phase. Conversely, when ATF4 expression was knocked down using siRNA in ECV304 cells, it protected the cells from radiation-induced apoptosis. These findings suggest that ATF4 may play a role in radiation-induced cell killing by inhibiting cell proliferation and promoting cell apoptosis. Conclusions: In this study, we found that radiation up-regulated the expression of ATF4. We used ATF4 knockdown and over-expression systems to show that ATF4 may play a role in radiation-induced cellular apoptosis.

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Targeting the ATF4 pathway in cancer therapy

Abstract: The authors provide a number of suggestions that may assist in the development of ATF4 inhibitors.

Cited by 119 publications

References 86 publications

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Stress-mediated translational control in cancer cells

Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation

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