Jørgen Sikkeland

• Sikkeland, Jørgen; Ng, Matthew; Nenseth, Hatice Zeynep; Ünal, Bilal; Qu, Su & Jin, Yang [Show all 8 contributors for this article] (2022). STAMP2 suppresses autophagy in prostate cancer cells by modulating the integrated stress response pathway. American Journal of Cancer Research. 12(1), p. 327–336. Full text in Research Archive Show summary

  Six Transmembrane Protein of Prostate 2 (STAMP2) is critical for prostate cancer (PCa) growth. We previously showed that STAMP2 regulates the expression of stress induced transcription factor ATF4, which is implicated in starvation-induced autophagy. We therefore investigated whether STAMP2 is involved in the regulation of autophagy in PCa cells. Here we show that STAMP2 suppresses autophagy in PCa cells through modulation of the integrated stress response axis. We also find that STAMP2 regulates mitochondrial respiration. These findings suggest that STAMP2 has significant metabolic effects through mitochondrial function and autophagy, both of which support PCa growth.

• 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.

• Sikkeland, Jørgen; Lindstad, Torstein; Nenseth, Hatice Zeynep; Dezitter, Xavier Gabriel M; Qu, Su & Muhumed, Ridhwan Mohamed [Show all 9 contributors for this article] (2019). Inflammation and ER stress differentially regulate STAMP2 expression and localization in adipocytes. Metabolism: Clinical and Experimental. ISSN 0026-0495. 93, p. 75–85. doi: 10.1016/j.metabol.2019.01.014. Full text in Research Archive Show summary

  Background Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obese mice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress. Methods 3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNFα. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays. Results ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNFα had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBPα-mediated STAMP2 expression. Conclusion These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.

• Sikkeland, Jørgen; Sheng, Xia; Jin, Yang & Saatcioglu, Fahri (2016). STAMPing at the crossroads of normal physiology and disease states. Molecular and Cellular Endocrinology. ISSN 0303-7207. 425, p. 26–36. doi: 10.1016/j.mce.2016.02.013. Full text in Research Archive
• Lindstad, Torstein; Qu, Su; Sikkeland, Jørgen; Jin, Yang; Kristian, Alexandr & Mælandsmo, Gunhild [Show all 8 contributors for this article] (2016). STAMP2 is required for human adipose-derived stem cell differentiation and adiposite-facilitated prostrate cancer grown in vivo. OncoTarget. 8(54), p. 91817–91827. doi: 10.18632/oncotarget.11131. Full text in Research Archive
• Ertunc, Meric Erikci; Sikkeland, Jørgen; Fenaroli, Federico; Griffiths, Gareth Wyn; Daniels, Melissa C. & Cao, Haiming [Show all 8 contributors for this article] (2015). Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity. Journal of Lipid Research. ISSN 0022-2275. 56(2), p. 423–434. doi: 10.1194/jlr.M055798. Full text in Research Archive
• Sikkeland, Jørgen; Jin, Yang & Saatcioglu, Fahri (2014). Methods to assess lipid accumulation in cancer cells. Methods in Enzymology. ISSN 0076-6879. 542, p. 407–423. doi: 10.1016/B978-0-12-416618-9.00021-2. Full text in Research Archive
• Sikkeland, Jørgen & Saatcioglu, Fahri (2013). Differential Expression and Function of Stamp Family Proteins in Adipocyte Differentiation. PLOS ONE. 8(7). doi: 10.1371/journal.pone.0068249. Full text in Research Archive Show summary

  Six transmembrane protein of prostate (Stamp) proteins play an important role in prostate cancer cell growth. Recently, we found that Stamp2 has a critical role in the integration of inflammatory and metabolic signals in adipose tissue where it is highly expressed and regulated by nutritional and metabolic cues. In this study, we show that all Stamp family members are differentially regulated during adipogenesis: whereas Stamp1 expression is significantly decreased upon differentiation, Stamp2 expression is increased. In contrast, Stamp3 expression is modestly changed in adipocytes compared to preadipocytes, and has a biphasic expression pattern during the course of differentiation. Suppression of Stamp1 or Stamp2 expression both led to inhibition of 3T3-L1 differentiation in concert with diminished expression of the key regulators of adipogenesis - CCAAT/enhancer binding protein alpha (C/ebpa) and peroxisome proliferator-activated receptor gamma (Ppar?). Upon Stamp1 knockdown, mitotic clonal expansion was also inhibited. In contrast, Stamp2 knockdown did not affect mitotic clonal expansion, but resulted in a marked decrease in superoxide production that is known to affect adipogenesis. These results suggest that Stamp1 and Stamp2 play critical roles in adipogenesis, but through different mechanisms. This is an open-access article distributed under the terms of the Creative Commons Attribution License.

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