Tetraspanins stimulate protein synthesis in myeloma cell lines

Abstract

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.

The shaping and functional consequences of the dosage effect landscape in multiple myeloma

“…Recently, dosage effects of protein translation and transport genes are reported for plasma cell leukemia, a cancer closely related to myeloma [31]. Overdrive of translation machines is a feature of cancer cell proliferation [32-34]. Dosage sensitivity of the genes in translation processes indicates their expression levels are not subject to tightly controlled dosage compensation and are susceptible to the influence of copy number alteration.…”

Tetraspanin CD82: a suppressor of solid tumors and a modulator of membrane heterogeneity

“…The hypermethylation of their gene promoters contributes to the silencing [32]. Overexpression of CD81-GFP and CD82-GFP fusions in MM cells causes massive autophagic, nonapoptotic death [33,34] by attenuating Akt/mTOR signaling [35], activating the unfolded protein response [34], and stimulating protein synthesis [36]. Notably, overexpression of GFP-CD81 and GFP-CD82 fusions in MM cells reduces cell-matrix adhesion and cell movement [33].…”

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

“…CD81 is a transmembrane cell surface protein. Some studies have revealed that CD81 expression predicts a poor prognosis for PCM patients . In this study, CD117 and CD81 expression was analyzed in 131 patients who received initial treatment for PCM, and the relationship between CD117/CD81 expression and patient prognosis was further evaluated.…”