Overexpression of tetraspanins affects multiple myeloma cell survival and invasive potential

Tohami, Tali; Drucker, Liat; Shapiro, Hava; Radnay, Judith; Lishner, Michael

doi:10.1096/fj.06-6610com

Cited by 52 publications

(61 citation statements)

References 26 publications

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“…Previously we have reported that reintroduction of the tetraspanins, CD81N1 and CD82N1, into CAG and RPMI 8226 MM cell lines resulted in significant non-apoptotic cell death compared with mock-transfected cells (Tohami et al, 2007). Acknowledging the necessity of MM cells to incur changes that support the intensive protein synthesis and ER -Golgi equilibrium typical to them, we hypothesised that the tetraspanins' effect may involve an autophagic form of cell death due to ER-stress and UPR activation.…”

Section: Resultsmentioning

confidence: 94%

“…Purified plasmids pEGFP-N1 (mock), CD81N1, and CD82N1 were separately introduced into RPMI 8226 and CAG cells as described previously (Tohami et al, 2007). Fluorescence (X10 000 events per analysis) was analysed by Coulter Flow Cytometer (FACS) (EPICS-XL, Beckman Coulter Inc., Fullerton, CA, USA) as detailed previously (Tohami et al, 2007).…”

Section: Transient Transfectionmentioning

confidence: 99%

“…Fluorescence (X10 000 events per analysis) was analysed by Coulter Flow Cytometer (FACS) (EPICS-XL, Beckman Coulter Inc., Fullerton, CA, USA) as detailed previously (Tohami et al, 2007).…”

Section: Transient Transfectionmentioning

confidence: 99%

“…Previously, we showed that MM cells and cell lines underexpress tetraspanin members, CD81 and CD82, compared with normal plasma and peripheral blood B cells (Tohami et al, 2004(Tohami et al, , 2007Drucker et al, 2006). Tetraspanin proteins facilitate the spatial organisation and localisation of multi-protein complexes in distinct membranal microdomains that are important to exteriorinterior cell signalling.…”

mentioning

confidence: 99%

“…The importance of CD81 and CD82 to MM was shown in a study that reintroduced these tetraspanins in fusion vectors with eGFP (CD81N1, CD82N1) into MM cell lines. The tetraspanin overexpression resulted in significant cell death, described as primarily necrotic and caspase-independent (Tohami et al, 2007).…”

mentioning

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.

show abstract

Section: Resultsmentioning

confidence: 94%

Section: Transient Transfectionmentioning

confidence: 99%

“…Fluorescence (X10 000 events per analysis) was analysed by Coulter Flow Cytometer (FACS) (EPICS-XL, Beckman Coulter Inc., Fullerton, CA, USA) as detailed previously (Tohami et al, 2007).…”

Section: Transient Transfectionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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Expression of CD81 and CD117 in plasma cell myeloma and the relationship to prognosis

Chen

Wang

et al. 2018

Cancer Medicine

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In this study, the immunophenotype was retrospectively analyzed in 131 patients who received initial treatment for plasma cell myeloma (PCM) and the relationships of CD81 and CD117 with the clinicopathologic characteristics and prognosis were further evaluated. The Kaplan and Meier method and Cox regression survival analysis model were used to determine whether CD117 and CD81 were factors affecting the overall survival (OS) and progression‐free survival (PFS) of PCM patients. CD117 and CD81 positivity was demonstrated in 35.88% and 40.46% of the 131 patients, respectively. Kaplan‐Meier analysis showed that CD117 and CD81 were potential predictors of a patient's prognosis. Specifically, CD117(+) patients had longer PFS (P = 0.033) and OS (P = 0.002), while CD81(+) patients had shorter PFS (P = 0.001) and OS (P = 0.002). CD117(+) and CD81(−) patients had the longest PFS [P = 0.0183 compared to the CD117(−)CD81(−)/CD117(+)CD81(+) group; P = 0.0007 compared to the CD117(−)CD81(+) group] and the longest OS [P = 0.0331 compared to the CD117(−)CD81(−)/CD117(+)CD81(+) group; P = 0.0005 compared to the CD117(−)CD81(+) group]. Our results show that CD81 is an independent factor affecting the OS and PFS of PCM patients, and CD117 is an independent factor affecting the OS of PCM patients. CD117‐positive and CD81‐negative patients with PCM have a better prognosis.

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The effect of microenvironmental factors on the development of myeloma cells

Márk

Varga

Tímár

et al. 2016

Hematological Oncology

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Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of monoclonal plasma cells (PCs) in the bone marrow and other tissues. Although there are several new therapies, MM remains fatal. The interaction between MM cells and the bone marrow microenvironment promotes drug resistance and cancer cells survival. In our present work, we compared the antigen expression pattern of normal and pathological PCs and investigated the possible connections between various surface receptors, adhesion molecules, and recurrent genetic aberrations. We showed that the expression of CD29, CD27, and CD81 is lower in MM cells than in normal PCs. We found correlation of chromosome 11 hyperdiploidity and the decrease of CD27 expression. We demonstrated that MM cells with CD20 positivity also have CD28 expression. Multiple myeloma patients with active CD29 showed better response to treatment. Our results suggest that these changes may result in an alteration of the interaction between stromal cell and MM cell facilitating cell survival and the development of a more aggressive and resistant phenotype.

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Overexpression of tetraspanins affects multiple myeloma cell survival and invasive potential

Cited by 52 publications

References 26 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

Expression of CD81 and CD117 in plasma cell myeloma and the relationship to prognosis

The effect of microenvironmental factors on the development of myeloma cells

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