Nora Pällmann

• Deng, Ke; Pällmann, Nora; Livgård, Marte; Kildal, Wanja; Pradhan, Manohar & Fazli, Ladan [Show all 10 contributors for this article] (2025). Endoplasmic reticulum stress-driven nucleotide catabolism fuels prostate cancer. Cancer Letters. ISSN 0304-3835. 630. doi: 10.1016/j.canlet.2025.217888. Full text in Research Archive Show summary

  Endoplasmic reticulum (ER) stress is a critical regulator of cancer cell metabolism and survival. In this study, we elucidate the coordinated roles of two key ER stress mediators, Activating Transcription Factor 4 (ATF4) and X-box Binding Protein 1 spliced (XBP1s), in regulating purine homeostasis in prostate cancer (PCa) cells. We demonstrate that ATF4 directly upregulates Molybdenum Cofactor Sulfurase (MOCOS), a key enzyme in purine catabolism, while XBP1s induces the expression of xanthine dehydrogenase (XDH), the principal MOCOS target in this pathway. Knockdown of MOCOS significantly impairs PCa cell proliferation as well as prostatosphere and colony formation in vitro, and inhibits tumor growth in preclinical mouse models of PCa. Mechanistically, MOCOS suppression leads to purine accumulation, disrupts pyrimidine synthesis, and causes nucleotide imbalance, resulting in replication fork stalling. This imbalance is also accompanied by a compromised glutathione-mediated antioxidant response, rendering the cells more susceptible to DNA damage. Importantly, targeting XDH, either genetically or biochemically, also significantly hinders PCa cell growth. Collectively, our data highlight the pivotal role of ER stress-mediated purine homeostasis in sustaining PCa cell growth.

• Pällmann, Nora; Ke, Deng; Livgård, Marte; Tesikova, Martina; Jin, Yixin & Frengen, Nicolai Sebastian [Show all 18 contributors for this article] (2021). Stress-mediated reprogramming of prostate cancer one-carbon cycle drives disease progression. Cancer Research. ISSN 0008-5472. 81(15), p. 4066–4078. doi: 10.1158/0008-5472.CAN-20-3956. Full text in Research Archive Show summary

  One-carbon (1C) metabolism has a key role in metabolic programming with both mitochondrial (m1C) and cytoplasmic (c1C) components. Here we show that activating transcription factor 4 (ATF4) exclusively activates gene expression involved in m1C, but not the c1C cycle in prostate cancer cells. This includes activation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression, the central player in the m1C cycle. Consistent with the key role of m1C cycle in prostate cancer, MTHFD2 knockdown inhibited prostate cancer cell growth, prostatosphere formation, and growth of patient-derived xenograft organoids. In addition, therapeutic silencing of MTHFD2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in preclinical prostate cancer mouse models. Consistently, MTHFD2 expression is significantly increased in human prostate cancer, and a gene expression signature based on the m1C cycle has significant prognostic value. Furthermore, MTHFD2 expression is coordinately regulated by ATF4 and the oncoprotein c-MYC, which has been implicated in prostate cancer. These data suggest that the m1C cycle is essential for prostate cancer progression and may serve as a novel biomarker and therapeutic target. Significance: These findings demonstrate that the mitochondrial, but not cytoplasmic, one-carbon cycle has a key role in prostate cancer cell growth and survival and may serve as a biomarker and/or therapeutic target.

• Pällmann, Nora; Livgård, Marte; Tesikova, Martina; Nenseth, Hatice Zeynep; Akkus, Erman & Sikkeland, Jørgen [Show all 20 contributors for this article] (2019). Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer. Oncogene. ISSN 0950-9232. 38, p. 6301–6318. doi: 10.1038/s41388-019-0879-2. Full text in Research Archive Show summary

  Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.

• Jin, Yang; Ling, Wang; Qu, Su; Sheng, Xia; Kristian, Alexandr & Mælandsmo, Gunhild [Show all 20 contributors for this article] (2015). STAMP2 increases oxidative stress and is critical for prostate cancer. EMBO Molecular Medicine. ISSN 1757-4676. 7(3), p. 315–331. doi: 10.15252/emmm.201404181. Full text in Research Archive Show summary

  The six transmembrane protein of prostate 2 (STAMP2) is an androgen‐regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage‐independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target.

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