Tetraspanins affect myeloma cell fate via Akt signaling and FoxO activation

Lishner, Michael; Zismanov, Victoria; Tohami, Tali; Tartakover-Matalon, Shelly; Elis, Avishay; Drucker, Liat

doi:10.1016/j.cellsig.2008.08.018

Cited by 15 publications

(27 citation statements)

References 57 publications

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“…Previously, we showed that the CD81N1/CD82N1 overexpression attenuated AKT activity and activated FoxO transcription factors (Lishner et al, 2008). In this project we again showed the involvement of JNK activity in the fate of transfected cells (Lishner et al, 2008). Taken together, these findings are compatible with a recent publication that depicted a role for FoxO1 in the death of ERstressed macrophages (Senokuchi et al, 2008).…”

Section: Discussionsupporting

confidence: 81%

“…Assessment of phosphorylated and total mTOR levels in CD81N1/CD82N1-transfected MM cell lines displayed decreased levels of active mTOR compared with mock-transfected control (24 h post-transfection, 35 -40%, Po0.05), which is in sync with autophagic activation ( Figure 2C). These findings are also in accordance with previous results that described a decrease in the number of tetraspanin-transfected MM cells expressing pmTOR (Lishner et al, 2008). Next, we assessed cellular levels of Beclin 1, an established component of the autophagic machinery (Cao and Klionsky, 2007), in the tetraspanin vs mock-transfected MM cell lines, but failed to determine significant changes (data not shown).…”

Section: Autophagic Death Induced By Cd81n1 and Cd82n1 In MM Cell Linessupporting

confidence: 79%

“…Yet, in this study, death was preceded by cell cycle arrest, whereas our experimental setting displayed no such effect (Tohami et al, 2007). Previously, we showed that the CD81N1/CD82N1 overexpression attenuated AKT activity and activated FoxO transcription factors (Lishner et al, 2008). In this project we again showed the involvement of JNK activity in the fate of transfected cells (Lishner et al, 2008).…”

Section: Discussionsupporting

confidence: 53%

“…Statistically significant differences (*Po0.05) are depicted. (Tohami et al, 2007;Lishner et al, 2008) studies, we showed that cell death, as well as the activation of UPR pathways, can be determined only in MM cell lines transfected with CD81N1 and CD82N1 eGFP fusion vectors and not with the empty eGFP construct (mock) or with the CD81C1 and CD82C1 oriented fusion plasmids (Tohami et al, 2007). Taken together, our results can be interpreted as presenting specific signals initiated by the cloned tetraspanins (in their N1 conformation).…”

Section: Discussionmentioning

confidence: 50%

“…Inhibition of MEK/ERK resulted in increased cell survival of CD81N1-transfected RPMI 8226 and CAG cells (24 h post-transfection, B1.26-fold change, Po0.05) as did inhibition of JNK, which resulted in increased survival of CD81N1-transfected RPMI 8226 (48 h) and CAG cells (24 h) (1.45-and 3.18-fold change, respectively; Po0.05) and of CD82N1-transfected RPMI 8226 cells (24 h, 1.27-fold change; Po0.05) (Figure 3). The involvement of JNK in the death of CD81N1-transfected CAG cells was reported by us previously in association with activation of Forkhead box O (FoxO) (Lishner et al, 2008).…”

Section: Autophagic Death Induced By Cd81n1 and Cd82n1 In MM Cell Linesmentioning

confidence: 99%

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Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

et al. 2009

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BACKGROUND: Multiple myeloma (MM) therapy is hindered by the interaction of the heterogeneous malignant plasma cells with their microenvironment and evolving drug resistance. We have previously shown that the membranal tetraspanins, CD81 and CD82, are under-expressed in MM cells and that their reintroduction causes massive non-apoptotic death. In this study, we aimed to characterise the tetraspanin-induced MM death. METHODS: Multiple myeloma cell lines were transiently transfected with eGFP -CD81N1/CD82N1 fusion proteins and assessed for death mode by flow cytometry (propidium iodide, ZVAD-fmk, 3MA), activation of unfolded protein response (UPR), and autophagy (immunoblot, RT -PCR). RESULTS: Cell death induced by CD81N1 and CD82N1 in MM cell lines was autophagic and involved endoplasmic reticulum (ER)-stress manifested by activation of UPR pathways, PERK (protein kinase-like ER kinase) and IRE1 (inositol-requiring 1). We also established the relative X-box binding protein 1 baseline expression levels in a panel of MM cell lines and their general dependence on autophagy for survival. Timeline of UPR cascades and cell fate supported our results. INTERPRETATION: This is the first publication implicating tetraspanins in UPR signalling pathways, autophagy, and autophagic death. Integration of our findings with published data highlights the unifying dependence of MM cells on ER -Golgi homoeostasis, and underscores the potential of tetraspanin complexes and ER-stress as leverage for MM therapy.

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Section: Discussionsupporting

confidence: 81%

Section: Autophagic Death Induced By Cd81n1 and Cd82n1 In MM Cell Linessupporting

confidence: 79%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 50%

Section: Autophagic Death Induced By Cd81n1 and Cd82n1 In MM Cell Linesmentioning

confidence: 99%

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Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

et al. 2009

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Tetraspanins stimulate protein synthesis in myeloma cell lines

Zismanov

Drucker

Attar-Schneider

et al. 2012

J of Cellular Biochemistry

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Intensive protein synthesis is a unique and differential trait of multiple myeloma (MM) cells. Previously we showed that tetraspanin (CD81, CD82) overexpression in MM cell lines attenuated Akt/mTOR cascades, activated UPR, and caused autophagic death, suggesting breach of protein homeostasis. Here, we explored the role of protein synthesis in the tetraspanin‐induced MM cell death. Contrary to attenuation of the major metabolic regulator, mTOR we determined elevated steady‐state levels of protein in CD81N1/CD82N1 transfected MM lines (RPMI‐8226, CAG). Elevated levels of immunoglobulins supported increased protein production in RPMI‐8226. Changes in cell morphology consistent with elevated protein synthesis were also determined (cell, nuclei, and nucleoli sizes and ratios). Increased levels of phospho‐rpS6 and decreased levels of phospho‐AMPK were consistent with increased translation but independent of mTOR. Involvement of p38 and its role in tetraspanin induced translation and cell death were demonstrated. Microarray analyses of tetraspanin transfected MM cell lines revealed activation of protein synthesis signaling cascades and signals implicated in ribosome biogenesis (snoRNAs). Finally, we showed tetraspanins elevated protein synthesis was instrumental to MM cells' death. This work explores and demonstrates that excessive protein translation can be detrimental to MM cell lines and therefore may present a therapeutic target. Proteostasis is particularly important in MM because it integrates the high levels of protein production unique to myeloma cells with critically important microenvironmental cues. We suggest that increasing translation may be the path of least resistance in MM and thus may afford a novel platform for strategically designed therapy. J. Cell. Biochem. 113: 2500–2510, 2012. © 2012 Wiley Periodicals, Inc.

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Tetraspanins and Cancer Metastasis

Zöller

2010

The Tumor Microenvironment

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Tetraspanins affect myeloma cell fate via Akt signaling and FoxO activation

Cited by 15 publications

References 57 publications

Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

Tetraspanins stimulate protein synthesis in myeloma cell lines

Tetraspanins and Cancer Metastasis

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