Lyn Facilitates Glioblastoma Cell Survival under Conditions of Nutrient Deprivation by Promoting Autophagy

Liu, Wei Michael; Huang, Ping; Kar, Niladri; Burgett, Monica E.; Muller-Greven, Gaelle; Nowacki, Amy S.; Distelhorst, Clark W.; Lathia, Justin D.; Rich, Jeremy; Kappes, John C.; Gladson, Candece L.

doi:10.1371/journal.pone.0070804

Cited by 33 publications

(18 citation statements)

References 51 publications

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“…Autophagy, a multi-step process that involves degradation of long-lived cellular proteins and organelles, is a genetically programmed, highly conserved process that occurs in eukaryotes from yeast to mammals. Recently, studies have shown that autophagy plays a vital role in protecting cells against adverse conditions (5)(6)(7), including irradiation (8). Inhibition of autophagy plays an active role in radiosensitization in several cancer cell types (9) as well as in NPC cells (10).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagy enhances the radiosensitivity of nasopharyngeal carcinoma by reducing Rad51 expression

Xie

et al. 2014

Oncology Reports

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Radiotherapy has long been considered as the mainstay of treatment for nasopharyngeal carcinoma (NPC). However, locoregional recurrence or distant metastasis may occur in some patients due to the radiation resistance of cancer cells. Autophagy plays a vital role in protecting cells against radiation. However, the mechanism of autophagy in radiation therapy remains obscure. In the present study, we demonstrated that suppression of autophagy related 5 (Atg5) aggravated ionizing radiation (IR)-induced DNA damage and apoptosis in human NPC cells without accelerating the cell cycle, whereas regulation of the cell cycle has been widely regarded as the most important determinant of IR sensitivity. Further study showed that inhibition of autophagy suppressed the mRNA expression of Rad51, a key protein of homologous recombination that has been demonstrated to play a critical role in the repair of DNA double-strand breaks induced by radiation. Moreover, suppression of Atg5 had no impact on the radiosensitivity when cells were pre-treated by the Rad51 inhibitor, and the enhanced radiosensitivity by Atg5 suppression was reversed by overexpression of Rad51 in human NPC cells. Our results suggest that inhibition of autophagy enhances the susceptibility of NPC cells to radiation by reducing Rad51 expression. Therefore, Rad51 targeted therapy may be investigated as a potential novel agent for the adjuvant treatment of traditional radiation of NPC.

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Section: Introductionmentioning

confidence: 99%

Inhibition of autophagy enhances the radiosensitivity of nasopharyngeal carcinoma by reducing Rad51 expression

Xie

et al. 2014

Oncology Reports

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“…Lyn is a member of the Src family of tyrosine kinases (SFKs) that is a pivotal signalling intermediary for signal transduction pathways involved in a broad range of cellular functions such as proliferation[1, 2], differentiation[3], cell migration[4], autophagy[5] and apoptosis[6]. The structure of the Lyn protein includes: (i) a unique N-terminal domain (SH4) that contains a myristoylation site and a palmitoylation site[7] required for membrane attachment, followed by (ii) two protein-protein interaction domains initially characterized in SFKs (SRC homology 2 and 3 domains, SH2 and SH3 respectively), and (iii) a kinase domain containing its catalytic activity.…”

Section: Introductionmentioning

confidence: 99%

The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway

Eldeeb

Fahlman

2014

Oncotarget

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The activation of apoptotic pathways results in the caspase cleavage of the Lyn tyrosine kinase to generate the N-terminal truncated LynΔN. This LynΔN fragment has been demonstrated to exert negative feedback on imatinib induced apoptosis in chronic myelogenous leukemia (CML) K562 cells. Our investigations focus on LynΔN stability and how reduced stability reduces imatinib resistance. As the proteolytical generated LynΔN has a leucine as an N-terminal amino acid, we hypothesized that LynΔN would be degraded by the N-end rule pathway. We demonstrated that LynΔN is unstable and that its stability is dependent on the identity of its N-terminus. Additionally we established that LynΔN degradation could be inhibited by either inhibiting the proteasome or knocking down the UBR1 and UBR2 ubiquitin E3 ligases. Importantly, we also demonstrate that LynΔN degradation by the N-end rule counters the imatinib resistance of K562 cells provided by LynΔN expression. Together our data suggest a possible mechanism for the N-end rule pathway having a link to imatinib resistance in CML. With LynΔN being an N-end rule substrate, it provides the first example that this pathway can also provide a pro-apoptotic function as previous reports have currently only demonstrated anti-apoptotic roles for the N-end rule pathway.

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“…The significant decrease in cell death with bevacizumab treatment at 48 h supports the concept that bevacizumab induces a pro-survival form of autophagy in the CD133 + cells. Autophagy is generally a survival mechanism by which cells that are stressed due to nutrient deprivation, absence of growth factors, or hypoxia metabolize organelles, misfolded proteins and aggregated proteins, thereby generating molecules that allow the cell to survive (33,47). Previously, others have reported an increase in autophagy on bevacizumab treatment of GBM cells cultured in media with growth factors or under hypoxic conditions (40,48), but the effect of bevacizumab on VEGF-A secreted by tumor cells was not examined.…”

Section: Discussionmentioning

confidence: 99%

Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival

Muller-Greven

Carlin

Burgett

et al. 2017

Clinical Cancer Research

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Purpose Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors. Experimental Design Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133+ cells derived from GBM tumors in vitro. Bevacizumab internalization, trafficking and effects on cell survival were analyzed using multi-label confocal microscopy, immunoblotting and cytotoxicity assays in the presence/absence of inhibitors. Results In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2+/CD44+-tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133+/Sox2+-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133+ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133+ cell survival. Conclusions We demonstrate that bevacizumab is internalized by Sox2+/CD44+-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133+ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A.

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Lyn Facilitates Glioblastoma Cell Survival under Conditions of Nutrient Deprivation by Promoting Autophagy

Cited by 33 publications

References 51 publications

Inhibition of autophagy enhances the radiosensitivity of nasopharyngeal carcinoma by reducing Rad51 expression

Inhibition of autophagy enhances the radiosensitivity of nasopharyngeal carcinoma by reducing Rad51 expression

The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway

Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival

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