Effect of serglycin suppression on proteostasis mechanisms in multiple myeloma cells
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Date
2026-06-12
Authors
Ζαφειρακόπουλος, Δημήτριος-Ηλίας
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Abstract
In malignancies, such as multiple myeloma (MM), aberrant expression of proteoglycans (PGs) and other extracellular matrix (ECM) macromolecules is observed, thus promoting ECM remodeling. The ECM serves as a three-dimensional network critical for tissue structure and cellular function. Serglycin (SRGN), the only known intracellular PG, was initially characterized for its role in the maturation of secretory granules and the regulation of cargo bioavailability in the ECM. Recent data have identified SRGN as a multifunctional regulator of oncogenic signaling and tumor cell phenotype. Previous studies from our laboratory demonstrated a correlation between increased SRGN expression and enhanced tumor aggressiveness across several malignancies.
In MM, SRGN influences cell survival and disease progression by interacting with components of the bone marrow microenvironment, thereby constituting a potential biomarker and therapeutic target. Elevated levels of unfolded proteins in the endoplasmic reticulum (ER) lumen are a common feature of malignant cells, a phenomenon known as ER stress. To cope with ER stress, the unfolded protein response (UPR) is activated, which is mediated by PERK, IRE1α, and ATF6, aiming to restore proteostasis through adaptive responses, such as protein folding and synthesis regulation. However, if these mechanisms fail and the stress is prolonged, the UPR shifts towards a terminal state that triggers apoptosis. In parallel with the UPR, the ubiquitin-proteasome system (UPS), responsible for removing misfolded or damaged proteins, is also activated. Together, they support cancer cell survival, proliferation, and therapy resistance. Targeting UPS or UPR components can disrupt proteostasis in tumors, offering promising therapeutic strategies.
The aim of the present work is to investigate the role of SRGN and UPR status in MM cell lines U266 and H929, both of which express high levels of SRGN and UPR markers. We observed that H929 maintain elevated levels of active UPR compared to U266 cells and exhibit rapid proliferation capacity. Both MM cell lines utilized UPR as a survival mechanism, as shown by the loss of viability induced by inhibiting each UPR branch. SRGN expression was silenced using siRNA, and the effects on key components of the UPR and UPS were assessed. SRGN silencing caused distinct changes in the expression and activation of key UPR and UPS components, indicating a role for SRGN in MM cell proteostasis through selective regulation of the UPR and UPS pathways. Nevertheless, SRGN silencing resulted in disrupted pro-survival UPR activity and induction of apoptosis, pinpointing its tumorigenic aspect in MM malignancy.
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Keywords
Multiple myeloma, Extracellular matrix, Serglycin, Unfolded protein response, Ubiquitin-proteasome system, Apoptosis