HERPUD1 mediates palmitic acid-induced UPR sustaining TNBC aggressiveness and is destabilized by CK2 pharmacological inhibition
Year: 2025
Type: article
Abstract: HERPUD1 is a protein of the endoplasmic reticulum (ER) that is sensitive to the unfolded protein response (UPR) induced during ER stress and has been linked to ER stress tolerance in cancer cells. Many tumors, including triple-negative breast cancer (TNBC), which lacks an effective treatment, display UPR activity as a malignancy trait. However, whether HERPUD1 provides an ER-dependent mechanistic link for tumorigenic agents and/or potential therapeutic targets remains unknown. To address these possibilities, we first analyzed HERPUD1 expression in breast cancer (BC) biopsies via immunohistochemistry and immunofluorescence, revealing significantly higher levels in BC, including luminal A and TNBC, compared to non-malignant tissue. In TNBC, in addition to epithelial cells, HERPUD1 associated with inflammatory infiltrates, highlighting its potential role in tumor progression. Palmitic acid (PA), a dietary saturated fatty acid, is an obesity-associated tumor risk factor that induces ER stress and activates UPR. Interestingly, MDA-MB-231 cells, but not other BC cell lines, specifically upregulate HERPUD1 together with XBP1s and ATF4, key UPR factors, in response to PA, whereas TG treatment elevated HERPUD1 across all tested cell lines. HERPUD1 silencing reduced TNBC cell proliferation, migration, and invasion while enhancing doxorubicin (DOX) cytotoxicity, in both 2D and 3D cell culture models. HERPUD1 ablation also elevated UPR activation under TG. In contrast, PA-induced stress led to reduced UPR activation and lower IL-6 and IL-8 levels in the absence of HERPUD1 expression. We identified CK2 as a kinase that regulates HERPUD1 stability via Ser-59 phosphorylation. Strikingly, inhibition of CK2 with CX-4945 not only reduced HERPUD1 levels but also increased the sensitivity of BC cells to DOX. HERPUD1-S59D phosphomimetic mutants showed opposite effects.Our findings establish HERPUD1 as a key mediator of PA-driven aggressiveness, dependent on the lipid-handling capacity of TNBC cells and reveals a mechanistic to lipid stress and tumor progression.
Source: Cell Death and Disease
Authors: Laura Hernández-Torres, Viviana A. Cavieres, Omar Cortés, Eloisa Arias-Muñoz, Francisca Cruzat-Arias, Jorge Catalán-Aguilera, Javiera Álvarez-Indo, Macarena Aguilera-Olguín, Ronny Hernández, Eduardo Silva-Pavez, Julio C. Tapia, Jorge Cancino, Carlos F. Lagos, Tammy P. Pástor, Abigail J. Galarza, Gonzalo A. Mardones, Manuel Varas-Godoy, Nicole Villarreal-Cruz, Franz Villarroel-Espindola, Isabel Saffie, Alfonso González, María José Barrera, Pamela Ehrenfeld, Patricia V. Burgos
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,990
Awards: G1258112970, G1311425653, G1319379912, G1890105052, CHARACTERIZATION OF THE TOLL-LIKE RECEPTORS EXPRESSION RELATED TO H. PYLORI DURING PREMALIGNANT AND MALIGNANT GASTRIC LESIONS INFLAMMATION AND HYPOXIA CROSSTALK, G2470358752, G2894738481, G2980239273, G3143102804, UNVEILING THE FUNCTIONAL ROLE SIGNALING AND BIOMARKER UTILITY OF KLK4 AND KLK12 IN BREAST CANCER, PARTITIONING OF THE ONCOPROTEIN GOLPH3 IN BIOMOLECULAR CONDENSATES BY LIQUID--LIQUID PHASE SEPARATION A MECHANISM FOR THE PHENOTYPIC PLASTICITY OF BREAST CANCER CELLS, LABORATORIO NACIONAL DE SUPERCOMPUTACION, EXPLORING THE LINK BETWEEN LYSOSOMAL PROTEIN FUCOSYLATION AND TAMOXIFEN RESISTANCE IN ESTROGEN RECEPTOR-POSITIVE BREAST CANCER CELLS, G4900135381, THE INTERPLAY BETWEEN PHOSPHORYLATION AND UBIQUITYLATION CONTROLS STABILIZATION OF HERPUD1 UNDER ER STRESS POSSIBLE IMPLICATIONS ON TNBC AGGRESSIVENESS, IMPACT OF SRC ACTIVATION MEDIATED BY FATTY ACIDS IN THE BIOGENESIS OF PRO-METASTATIC EXOSOMES IN OVARIAN CANCER CELLS., G5881617275, COGNITIVE DYSFUNCTION MECHANISMS OF ANTI-RIBOSOMAL P PROTEIN ANTIBODIES IN SYSTEMIC LUPUS ERYTHEMATOSUS, UNIDAD DE MICROSCOPIA AUTOMATIZADA DE ALTO RENDIMIENTO Y ANALISIS DE ALTO CONTENIDO DE FENOTIPOS CELULARES COMPLEJOS CON APLICACION EN BIOMEDICINA., G7421283897, A PHOSPHO-SWITCH IN ENDOTHELIN-CONVERTING ENZYME-1C MODULATES AGGRESSIVENESS OF COLORECTAL CANCER CELLS, THE ROLE OF COMPLEX I/AMPK/BETA1-INTEGRIN PATHWAY ON THE EXTRACELLULAR MATRIX (ECM)-DETACHMENT AND THEIR IMPLICATION IN BREAST CANCER METASTASIS, PRO-INFLAMMATORY CYTOKINES DECREASE UNSATURATED CARDIOLIPIN LEVELS AND/OR MITOPHAGY PROMOTING MITOCHONDRIAL DAMAGE AND ITS EXTRACELLULAR RELEASE IN SALIVARY EPITHELIAL CELLS OF SJOGREN'S SYNDROME PATIENTS., CENTRO CIENTIFICO TECNOLOGICO DE EXCELENCIA CIENCIA & VIDA (CIENCIA & VIDA), ROL DE HERPUD1 EN LA AGRESIVIDAD DEL CANCER DE MAMA TRIPLE NEGATIVO EN PRESENCIA DE DIFERENTES FARMACOS QUIMIOTERAPEUTICOS
OpenAlex ID: W4415914787