Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy

Talebi, Ali; Dehairs, Jonas; Rambow, Florian; Rogiers, Aljosja; Nittner, David; Derua, Rita; Vanderhoydonc, Frank; Duarte, João; Bosisio, Francesca Maria; Eynde, Kathleen Van den; Nys, Kris; Vara-Pérez, Mónica; Agostinis, Patrizia; Waelkens, Etienne; Oord, Joost van den; Fendt, Sarah-Maria; Marine, Jean–Christophe; Swinnen, Johannes V.

doi:10.1038/s41467-018-04664-0

Cited by 104 publications

(101 citation statements)

References 67 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with this, acute treatment with vemurafenib or trametinib reduced transcript level of SLC7A11 in BRAF V600E melanoma cells [190]. Others have identified changes of the lipid metabolism, such as accumulation of PUFAs, in melanoma cells exposed to vemurafenib [191]. BAY 87-2243, an inhibitor that impairs OXPHOS by targeting the mitochondrial complex I, cooperated with vemurafenib in attenuation of melanoma tumor growth in vivo [187], although this could be related to induction of both ferroptosis and necroptosis as reported by others [152].…”

Section: Ferroptosis In Melanomamentioning

confidence: 68%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

View full text Add to dashboard Cite

Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

show abstract

Section: Ferroptosis In Melanomamentioning

confidence: 68%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Previous reports have shown that fatostatin inhibits proliferation and induces apoptosis in ER+ breast cancer cells via the activation of endoplasmic reticulum (ER) stress and lipid accumulation, under lipid-sufficient conditions [47]; this could be attributed to the fact that fatostatin directly and negatively impacted on the lipid-synthesis and metabolic pathways [48]. This is supported by a previous study where ectopic expression of SREBP1 resulted in increased levels of lipogenic genes, such as fatty acid synthase (FASN), stearoyl CoA desaturase (SCD), and acetyl-CoA carboxylase-1 (ACC), and augmented lipogenesis and sphere formation in MCF10A stem-like cells [49].…”

Section: Discussionmentioning

confidence: 99%

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Huang

Hsu

et al. 2019

Cells

View full text Add to dashboard Cite

Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Cells 2020, 9, 7 2 of 15Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

show abstract

“…The short-lived anti-cancer effects noticed in BRAFV600E-mutant metastatic melanoma treated with BRAF inhibitors are good examples [169,170]. According to Talebi et al (2018) [171] the lipogenic pathway, mediated by Sterol Regulatory Element Binding Protein (SREBP-1) is culpable in oncogenic BRAF constitutive activation and instrumental to therapy resistance. SREBP-1 inhibitors together with BRAF inhibitors should be adopted to defeat resistance to BRAFV600E-targeted therapy [171].…”

Section: Resistance To Braf-targeted Therapymentioning

confidence: 99%

Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

Metibemu

Akinloye

Akamo

et al. 2019

Egypt J Med Hum Genet

View full text Add to dashboard Cite

Background: Receptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to the tyrosine residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression of RTK customarily leads to cell growth dysfunction, which is connected to tumor takeover, angiogenesis, and metastasis. Understanding the structure, mechanisms of adaptive and acquired resistance, optimizing inhibition of RTKs, and eradicating cum minimizing the havocs of quiescence cancer cells is paramount. MainText: Tyrosine kinase inhibitors (TKIs) vie with RTKs ATP-binding site for ATP and hitherto reduce tyrosine kinase phosphorylation, thus hampering the growth of cancer cells. TKIs can either be monoclonal antibodies that compete for the receptor's extracellular domain or small molecules that inhibit the tyrosine kinase domain and prevent conformational changes that activate RTKs. Progression of cancer is related to aberrant activation of RTKs due to due to mutation, excessive expression, or autocrine stimulation. Conclusions:Understanding the modes of inhibition and structures of RTKs is germane to the design of novel and potent TKIs. This review shed light on the structures of tyrosine kinases, receptor tyrosine kinases, tyrosine kinase inhibitors, minimizing imatinib associated toxicities, optimization of tyrosine kinase inhibition in curtailing quiescence in cancer cells and the prospects of receptor tyrosine kinase based treatments.

show abstract

Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy

Cited by 104 publications

References 67 publications

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

Contact Info

Product

Resources

About