bims-miptne 2024-11-10 papers

Cell Commun Signal. 2024 Nov 06. 22(1): 533

Breast cancer cells utilize T3 to trigger proliferation through cellular Ca2+ modulation.

Ines Tawfik, Katharina Schlick, Julian Ostaku, Doruntina Bresilla, Sonja Gabrijelčič, Benjamin Gottschalk, Alwin Sokolowski, Ernst Malle, Katarina Kalinova, Martin Hirtl, Corina T Madreiter-Sokolowski.

High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca2+ handling proteins, thereby boosting mitochondrial Ca2+ uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca2+-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca2+ uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer.

Keywords: Breast cancer; Calcium homeostasis; IP3R3; Mitochondria; Thyroid hormone receptor α; Thyroid hormones

DOI: https://doi.org/10.1186/s12964-024-01917-y

Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00135-1. [Epub ahead of print] 101977

The multifaceted modulation of mitochondrial metabolism in tumorigenesis.

Rajendiran Keerthiga, Yafang Xie, Desheng Pei, Ailing Fu.

Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.

Keywords: EMT-MET transition; OXPHOS; Oncometabolites; Plasticity; TCA cycle; Tumorigenesis

DOI: https://doi.org/10.1016/j.mito.2024.101977

Exp Cell Res. 2024 Oct 30. pii: S0014-4827(24)00404-X. [Epub ahead of print]443(1): 114313

The mode of action of sorafenib in MDA-MB-231 breast carcinoma cells involves components of apoptotic, necroptotic and autophagy-dependent cell death pathways.

Gudapureddy Radha, Pratyush Pragyandipta, Pradeep Kumar Naik, Manu Lopus.

We report the identification of an interesting mode of action by sorafenib (SF) (Nexavar) in triple-negative breast adenocarcinoma MDA-MB-231 cells. The dying cells presented features of apoptosis, such as externalization of phosphatidylserine and cleaved caspase-3, and autophagy-mediated cell death, such as formation of autophagosomes and autolysosomes, the overexpression of LC3-II, and the presence of LAMP1-positive vacuoles, while displaying insufficient autophagic flux. Components of endoplasmic reticulum stress (ER stress; PERK and CHOP) and of necroptosis (p-MLKL) were also elevated considerably. Investigating potential target proteins that could modulate this form of cell death, we next investigated the role of tubulin disruption, which is known to induce necroptosis, apoptosis, and autophagy-dependent cell death. Interactions of SF with purified tubulin were investigated in detail using a combination of cellular and biophysical assays, transmission electron microscopy, and computer simulations. A marked reduction in the intrinsic tryptophan fluorescence of tubulin, a concentration-dependent elevation of anilinonaphthalene sulfonate-tubulin complex fluorescence, electron micrographs of deformed in vitro-assembled microtubules, and disrupted and hyper-stabilized cellular microtubules evinced the ability of SF to target tubulin and disrupt cellular microtubules. Molecular docking and molecular dynamic simulations positioned the drug between the α and β subunits of tubulin with considerable stability (ΔGbind, -31.43 kcal/mol), suggesting that drug-induced perturbation of tubulin could contribute to this mode of cell death.

Keywords: Apoptosis; Autophagy; Microtubule; Necroptosis; Non-apoptotic cell death; Sorafenib

DOI: https://doi.org/10.1016/j.yexcr.2024.114313

J Cell Biol. 2025 Jan 06. pii: e202402107. [Epub ahead of print]224(1):

Ca2+ tunneling architecture and function are important for secretion.

Raphael J Courjaret, Larry E Wagner, Rahaf R Ammouri, David I Yule, Khaled Machaca.

Ca2+ tunneling requires both store-operated Ca2+ entry (SOCE) and Ca2+ release from the endoplasmic reticulum (ER). Tunneling expands the SOCE microdomain through Ca2+ uptake by SERCA into the ER lumen where it diffuses and is released via IP3 receptors. In this study, using high-resolution imaging, we outline the spatial remodeling of the tunneling machinery (IP3R1; SERCA; PMCA; and Ano1 as an effector) relative to STIM1 in response to store depletion. We show that these modulators redistribute to distinct subdomains laterally at the plasma membrane (PM) and axially within the cortical ER. To functionally define the role of Ca2+ tunneling, we engineered a Ca2+ tunneling attenuator (CaTAr) that blocks tunneling without affecting Ca2+ release or SOCE. CaTAr inhibits Cl- secretion in sweat gland cells and reduces sweating in vivo in mice, showing that Ca2+ tunneling is important physiologically. Collectively our findings argue that Ca2+ tunneling is a fundamental Ca2+ signaling modality.

DOI: https://doi.org/10.1083/jcb.202402107

Biochim Biophys Acta Mol Basis Dis. 2024 Oct 31. pii: S0925-4439(24)00551-9. [Epub ahead of print]1871(1): 167557

The IP3R inhibitor desmethylxestospongin B reduces tumor cell migration, invasion and metastasis by impairing lysosome acidification and β1-integrin recycling.

Galdo Bustos, Ulises Ahumada-Castro, Eduardo Silva-Pavez, Hernán Huerta, Andrea Puebla, Camila Quezada, Pablo Morgado-Cáceres, César Casanova-Canelo, Natalia Smith-Cortinez, Maša Podunavac, Cesar Oyarce, Alvaro Lladser, Paula Farias, Alenka Lovy, Jordi Molgó, Vicente A Torres, Armen Zakarian, J César Cárdenas.

Cancer is the second leading cause of death worldwide. >90 % of cancer-related deaths are due to metastasis, a process that depends on the ability of cancer cells to leave the primary tumor, migrate, and colonize different tissues. Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays an essential role in maintaining the homeostasis of cancer cells and the sustained proliferation. Desmethylxestospongin B (dmXeB) is a specific inhibitor of the IP3R that selectively arrests cell proliferation and promotes cancer cell death at high concentrations. However, whether migration, invasion and metastasis can be affected by this drug is unknown. Here, by using the highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231, we demonstrate that a prolonged inhibition of IP3R-mediated Ca2+ signals with dmXeB significantly reduces cell migration and invasion in vitro and metastasis in vivo. We found that this phenomenon was independent of the bioenergetic control of IP3R over the mitochondria and AMPK activation. Furthermore, employing a tandem LC3-GFP-mcherry assay, we found that prolonged inhibition of IP3R with dmXeB leads to diminished autophagic flux. This reduction can be attributed to impaired lysosomal acidification, as evidenced by assessments using DQ-BSA and pHrodo. Since cell migration requires appropriate assembly and disassembly of focal adhesions, along with the internalization and recycling of integrins via autophagy, we explored the dependency of integrin recycling from autophagosomes, finding that IP3R inhibition with dmXeB impaired the recycling of β1-integrins, which accumulated within autophagosomes. Our findings reveal an unexpected effect of IP3R inhibition with dmXeB in cancer cells that could represent a novel therapeutic strategy for the treatment of cancer metastasis.

Keywords: Breast cancer cell migration; Calcium signaling; Inositol 1,4,5-trisphosphate receptors; Lysosomes; Metastasis

DOI: https://doi.org/10.1016/j.bbadis.2024.167557