Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells

Bollu, Lakshmi Reddy; Ren, Jiangong; Blessing, Alicia M.; Katreddy, Rajasekhara Reddy; Gao, Guang; Xu, Lei; Wang, JinRong; Su, Fei; Zhang, Weihua

doi:10.4161/cc.29338

Cited by 48 publications

(42 citation statements)

References 58 publications

(75 reference statements)

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“…The same authors, in a previous study, described that FASN-dependent palmitoylation also activates mitochondrial EGFR and promotes cell survival whereas its inhibition leads to apoptosis (46). Furthermore, phosphorylation and activation of FASN by direct interaction with members of the EGFR family have already been described (46). These in vitro results together with TNBC patient sample study supported the evaluation of the antitumor efficacy of cetuximab in combination with the FASN inhibitor EGCG in doxorubicinsensitive and -resistant TNBC orthoxenografts in vivo.…”

Section: Discussionsupporting

confidence: 73%

“…In addition, Bollu and colleagues recently found that FASNdependent palmitoylation of EGFR is required for EGFR dimerization and kinase activation (45). The same authors, in a previous study, described that FASN-dependent palmitoylation also activates mitochondrial EGFR and promotes cell survival whereas its inhibition leads to apoptosis (46). Furthermore, phosphorylation and activation of FASN by direct interaction with members of the EGFR family have already been described (46).…”

Section: Discussionmentioning

confidence: 95%

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Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Giró-Perafita

Palomeras

Lum

et al. 2016

Clinical Cancer Research

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Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC.Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models.Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity.Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 95%

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Giró-Perafita

Palomeras

Lum

et al. 2016

Clinical Cancer Research

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“…Of note, EGF stimulation also induces palmitoylation of mitochondrial EGFR, which, in turn, favors fusion of mitochondria (Bollu et al ., ). EGFR, independently of its kinase activity, interacts with the fatty acid synthase, stimulating de novo synthesis of palmitate (Bollu et al ., ). This finding points to the involvement of the EGFR in the regulation of cell metabolism and supports the existence of a signaling‐metabolic wiring that plays a critical role in cancer.…”

Section: Noncanonical Kinase‐dependent and Kinase‐independent Egfr Fumentioning

confidence: 97%

Emerging functions of the EGFR in cancer

2017

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The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as ‘noncanonical’) functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand‐induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress‐induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.

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“…EGF also stimulates a role for mitochondrial EGFR in the fission and redistribution of mitochondria, which is associated with enhanced cancer cell motility [94]. Alternatively, activation of cell surface EGFR has been proposed to stimulate de novo synthesis of palmitate that in turn activates mitochondrial EGFR to promote mitochondrial fusion and cancer cell survival [95]. Mitochondrial localization of EGFR can also be independent of EGFR endocytosis, suggesting direct EGFR delivery to mitochondria upon synthesis [13].…”

Section: Stress-induced Mitochondrial Translocation Of Egfrmentioning

confidence: 99%

Stress-Induced EGFR Trafficking: Mechanisms, Functions, and Therapeutic Implications

Tan

Lambert

Rapraeger

et al. 2016

Trends in Cell Biology

156

174

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Epidermal growth factor receptor (EGFR) has fundamental roles in normal physiology and in cancer, making it a rational target for cancer therapy. Surprisingly, however, inhibitors that target canonical, ligand-stimulated EGFR signaling have proven to be largely ineffective in treating many EGFR-dependent cancers. Recent evidence indicates that both intrinsic and therapy-induced cellular stress triggers robust, non-canonical pathways of ligand-independent EGFR trafficking and signaling, which provides cancer cells with a survival advantage and resistance to therapeutics. Here we review the mechanistic regulation of non-canonical EGFR trafficking and signaling, the pathological and therapeutic stresses that activate it, and discuss the implications of this pathway in clinical treatment of EGFR-overexpressing cancers.

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Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells

Cited by 48 publications

References 58 publications

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Emerging functions of the EGFR in cancer

Stress-Induced EGFR Trafficking: Mechanisms, Functions, and Therapeutic Implications

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