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• 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.

• Kuzu, Omer; Granerud, Lars Jørgen Tvenge & Saatcioglu, Fahri (2025). Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations. Signal Transduction and Targeted Therapy. ISSN 2095-9907. 10(1). doi: 10.1038/s41392-025-02439-w. Full text in Research Archive Show summary

  Abstract Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function. This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network—an integrated system of molecular chaperones, folding enzymes, and degradation machineries. Disruptions in this network lead to dysproteostasis, a pathological state implicated in a growing list of human diseases, including neurodegenerative disorders, metabolic syndromes, and cancer. In this review, we provide a comprehensive and multidimensional analysis of protein folding biology, tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics. We explore the historical progression of protein folding research, including landmark discoveries of secondary structure, chaperone biology, and energy landscape theory. We detail the roles of key molecular chaperones across cytosolic, mitochondrial, and endoplasmic reticulum compartments, emphasizing their collaborative actions in protein folding and quality control. We also discuss the multifactorial causes of protein misfolding—from genetic mutations to aging and oxidative stress—and examine the pathological consequences, paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity. We then examine therapeutic innovations targeting proteostasis, including chaperone modulators, proteostasis pathway inhibitors, and emerging strategies to increase proteome resilience. By consolidating insights at the molecular, cellular, and systems levels, this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.

• Ünal, Bilal; Kuzu, Omer; Yang, Jin; Osorio, Daniel; Kildal, Wanja & Pradhan, Manohar [Show all 14 contributors for this article] (2024). Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer. Nature Communications. 15(1), p. 1–21. doi: 10.1038/s41467-024-53039-1. Full text in Research Archive Show summary

  Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa.

• Pihlstrøm, Nicklas; Jin, Yang; Nenseth, Hatice Zeynep; Kuzu, Omer Faruk & Saatcioglu, Fahri (2021). Stamp2 expression mediated by cytokines attenuates their growth-limiting effects in prostate cancer cells. Cancers. 13(7). doi: 10.3390/cancers13071579. Full text in Research Archive Show summary

  Inflammatory events and dysregulated cytokine expression are implicated in prostate cancer (PCa), but the underlying molecular mechanisms are poorly understood at present. We have previously identified six transmembrane protein of the prostate 2 (STAMP2, also known as STEAP4) as an androgen-regulated gene, as well as a key regulator of PCa growth and survival. STAMP2 is also regulated by, and participates in, inflammatory signaling in other tissues and pathologies. Here, we show that the proinflammatory cytokines interleukin 6 (IL-6) and Interleukin 1 beta (IL-1β) significantly increase and strongly synergize in promoting STAMP2 expression in PCa cells. The two cytokines increase androgen-induced STAMP2 expression, but not expression of other known androgen target genes, suggesting a unique interplay of androgens and cytokines in regulating STAMP2 expression. Interestingly, STAMP2 knockdown significantly increased the ability of IL-6 and IL-1β to inhibit PCa cell growth in vitro. These results suggest that STAMP2 may represent a unique node through which inflammatory events mediate their effects on PCa growth and survival.

• 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.

• Sheng, Xia; Nenseth, Hatice Zeynep; Qu, Su; Kuzu, Ömer Faruk; Frahnow, Turid & Simon, Lukas [Show all 16 contributors for this article] (2019). IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nature Communications. 10:323, p. 1–12. doi: 10.1038/s41467-018-08152-3. Full text in Research Archive Show summary

  Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.

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• Sheng, Xia; Nenseth, Hatice Zeynep; Qu, Su; Kuzu, Omer; Frahnow, Turid & Simon, Lukas [Show all 16 contributors for this article] (2024). Correction to: IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling (Nature Communications, (2019), 10, 1, (323), 10.1038/s41467-018-08152-3). Nature Communications. 15(1). doi: 10.1038/s41467-024-50645-x. Full text in Research Archive

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