Biology subjects

Weissenrieder, J. S.

Publications and source records attributed to Weissenrieder, J. S..

3 recordsLinked to original sources

bioRxiv2024

Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity

Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF{beta}. Snail re-expression and TGF{beta} treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

cancer biology↗

bioRxiv2023

The mitochondrial Ca2+ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation

The mitochondrial uniporter (MCU) Ca2+ ion channel represents the primary means for Ca2+ uptake into mitochondria. Here we employed in vitro and in vivo models with MCU genetically eliminated to understand how MCU contributes to tumor formation and progression. Transformation of primary fibroblasts in vitro was associated with increased MCU expression, enhanced mitochondrial Ca2+ uptake, suppression of inactivating-phosphorylation of pyruvate dehydrogenase, a modest increase of basal mitochondrial respiration and a significant increase of acute Ca2+-dependent stimulation of mitochondrial respiration. Inhibition of mitochondrial Ca2+ uptake by genetic deletion of MCU markedly inhibited growth of HEK293T cells and of transformed fibroblasts in mouse xenograft models. Reduced tumor growth was primarily a result of substantially reduced proliferation and fewer mitotic cells in vivo, and slower cell proliferation in vitro associated with delayed progression through S-phase of the cell cycle. MCU deletion inhibited cancer stem cell-like spheroid formation and cell invasion in vitro, both predictors of metastatic potential. Surprisingly, mitochondrial matrix Ca2+ concentration, membrane potential, global dehydrogenase activity, respiration and ROS production were unchanged by genetic deletion of MCU in transformed cells. In contrast, MCU deletion elevated glycolysis and glutaminolysis, strongly sensitized cell proliferation to glucose and glutamine limitation, and altered agonist-induced cytoplasmic Ca2+ signals. Our results reveal a dependence of tumorigenesis on MCU, mediated by a reliance on mitochondrial Ca2+ uptake for cell metabolism and Ca2+ dynamics necessary for cell-cycle progression and cell proliferation.

cancer biology↗

bioRxiv2019

Thioridazine as an Anticancer Therapeutic: Interplay with the Isoprenoid Biosynthetic Pathway

Glioblastoma multiforme is a form of cancer with poor survival prognosis and few treatment options. The cerebrovascular barrier complicates the delivery of chemotherapeutic agents and contributes to poor treatment response in patients with this disease. Recently, dopamine D2 receptor antagonizing compounds, including the FDA-approved phenothiazine, thioridazine, were identified as potential anticancer therapeutics, but their mechanism of action is as yet poorly understood. We investigated the hypothesis that the cytotoxicity of thioridazine may be tied to disruption of lipid metabolism, specifically the synthesis of isoprenoids and cholesterol by the isoprenoid biosynthetic pathway. We show that, while pathway inhibitors lovastatin and zoledronate can sensitize U87MG and U251MG cells to thioridazine treatment, the addition of pathway intermediates cannot prevent thioridazines cytotoxic effects. Treatment with methyl-schweinfurthin G, which is known to disrupt lipid trafficking, is able to sensitize these cell lines as well, suggesting that cholesterol availability or localization may be involved in these effects. However, all measured effects were of very small, biologically insignificant magnitude and thus findings are of limited utility.

pharmacology and toxicology↗