EGFR tyrosine kinase inhibition induces autophagy in cancer cells

Fung, Cha-Chi; Chen, Xing; Grandis, Jennifer R.; Duvvuri, Umamaheswar

doi:10.4161/cbt.22002

Cited by 92 publications

(93 citation statements)

References 26 publications

(35 reference statements)

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“…[12][13][14] Levine's group further demonstrated that the mechanism behind this observation is due to the binding of EGFR with BECN1. 12 Our data showed that EGFR controls the level of autophagic flux in hypoxia; a low level of autophagic flux protects cells from death whereas a high level of autophagic flux promotes cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of EGFR inhibited autophagy [12][13][14] by triggering the binding of EGFR to the autophagy protein BECN1. 12 We examined the interaction between EGFR and BECN1 by immunoprecipitation (IP) in U87 cells.…”

Section: Egfr Regulates Hypoxia-induced Autophagy and Cell Deathmentioning

confidence: 99%

“…[9][10][11][12] EGFR suppresses autophagy in different cell types [12][13][14] through the activation of EGFR which leads to EGFR binding to the autophagy protein BECN1 (Beclin 1, autophagy related) and subsequent tyrosine phosphorylation of BECN1 at multiple sites. This causes the suppression of BECN1-associated PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3) kinase activity and inhibition of autophagy.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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(2016) Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia, Autophagy, 12:6, 1029-1046, DOI: 10.1080/15548627.2016 ABSTRACTAutophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia.

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Section: Discussionmentioning

confidence: 99%

Section: Egfr Regulates Hypoxia-induced Autophagy and Cell Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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“…Another study shows that defective autophagy may be a mechanism to confer resistance to inhibition of EGFR tyrosine kinase by cancer drugs. The co-treatment of these cells with rapamycin, a known inducer of autophagy, can partially restore sensitivity to EGFR tyrosine kinase inhibition, which suggests that activation of autophagy may be a viable strategy to treat or co-treat these types of cancer (20). These experiments suggest that a high level of autophagy might result in cell death in some types of tumors.…”

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confidence: 81%

Lower mRNA and Protein Expression Levels of LC3 and Beclin1, Markers of Autophagy, were Correlated with Progression of Renal Clear Cell Carcinoma

Deng

Wang

et al. 2013

Japanese Journal of Clinical Oncology

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Objective: The aim of this study was to examine the level of autophagy in renal clear cell carcinoma, stratify by clinicopathologic grades and stages and compare it with healthy renal tissue in order to hypothesize on the role of autophagy in the proliferation of renal clear cell carcinoma. Methods: Renal clear cell carcinoma tissue and matched adjacent tissue were collected from 52 patients who had received surgical resection. Autophagosomes were visualized in both renal clear cell carcinomas and adjacent tissue by transmission electron microscopy. Expression of the markers of autophagy, Beclin1 and LC3, was detected by a reverse transcription -polymerase chain reaction. Beclin1 and LC3 protein levels were examined by immunohistochemistry and western blot, and the correlation between autophagy levels and clinicopathologic data was analyzed. Results: Autophagy was down-regulated in renal clear cell carcinomas compared with matched adjacent tissue as measured by the reverse transcriptase-polymerase chain reaction, immunohistochemistry and western blot analyses. Clinicopathologic analyses indicated that advanced or metastatic renal clear cell carcinomas were associated with a lower expression of autophagy compared with localized renal clear cell carcinomas. Similarly, the Fuhrman nuclear grade of renal clear cell carcinomas was negatively correlated with the level of autophagy. Stage, grade and the level of LC3 II were significant factors for prognosis and the low level of LC3 II was associated with poor prognosis of renal clear cell carcinomas. Conclusions:The results indicate that autophagy is suppressed in renal clear cell carcinomas. The lower levels of autophagy are correlated with the higher stages and grades of renal clear cell carcinomas. Furthermore, a low level of LC3 II indicates poor prognosis of renal clear cell carcinoma. This is suggestive of association between the low level of autophagy and progression of renal clear cell carcinoma.

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“…Autophagy is generally thought to prevent cancer initiation but is also positioned to promote cancer cell survival upon metabolic stress (Brech et al, 2009; White, 2012). Rapamycin, an autophagy inducer, exhibits cytotoxic effects in cancer cells treated with EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib (Fung et al, 2012; Gorzalczany et al, 2011). However, autophagy induced by EGFR TKIs or neutralizing antibody shows cytoprotective roles (Choi et al, 2013; Dragowska et al, 2013; Eimer et al, 2011; Han et al, 2011; Li and Fan, 2010; Li et al, 2010b; Sobhakumari et al, 2013; Zou et al, 2013), suggesting that EGFR TKIs (or neutralizing antibody) may induce autophagy by a mechanism distinct from rapamycin.…”

Section: Introductionmentioning

confidence: 99%

A Kinase-Independent Role for EGF Receptor in Autophagy Initiation

Tan

Thapa

Sun

et al. 2015

Cell

196

220

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The Epidermal Growth Factor Receptor (EGFR) is upregulated in numerous human cancers. Inhibition of EGFR signaling induces autophagy in tumor cells. Here we report an unanticipated role for the inactive EGFR in autophagy initiation. Inactive EGFR interacts with the oncoprotein LAPTM4B that is required for the endosomal accumulation of EGFR upon serum starvation. Inactive EGFR and LAPTM4B stabilize each other at endosomes and recruit the exocyst subcomplex containing Sec5. We show that inactive EGFR, LAPTM4B, and the Sec5 subcomplex are required for basal and starvation induced autophagy. LAPTM4B and Sec5 promote EGFR association with the autophagy inhibitor Rubicon, which in turn disassociates Beclin 1 from Rubicon to initiate autophagy. Thus, the oncoprotein LAPTM4B facilitates the role of inactive EGFR in autophagy initiation. This pathway is positioned to control tumor metabolism and promote tumor cell survival upon serum deprivation or metabolic stress.

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EGFR tyrosine kinase inhibition induces autophagy in cancer cells

Abstract: Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer; mTOR, mammalian target of rapamycin; LC3, microtubule-associated proteins 1A/1B light chain 3A

Cited by 92 publications

References 26 publications

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Lower mRNA and Protein Expression Levels of LC3 and Beclin1, Markers of Autophagy, were Correlated with Progression of Renal Clear Cell Carcinoma

A Kinase-Independent Role for EGF Receptor in Autophagy Initiation

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