The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation

Journal article


Parzych, K., Saavedra-García, P., Valbuena, G.N., Al-Sadah, H.A., Robinson, M.E., Penfold, L., Kuzeva, D.M., Ruiz-Tellez, A,, Loaiza, S,, Holzmann, V., Caputo Galarce, V., Johnson, D.C., Kaiser, M.F., Karadimitris, A,, Lam, E.W.F, Chevet, E., Feldhahn, N., Keun, H.C. and Auner, H.W. (2019). The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation. Oncogene. 38, p. 3216–3231. https://doi.org/10.1038/s41388-018-0651-z
AuthorsParzych, K., Saavedra-García, P., Valbuena, G.N., Al-Sadah, H.A., Robinson, M.E., Penfold, L., Kuzeva, D.M., Ruiz-Tellez, A,, Loaiza, S,, Holzmann, V., Caputo Galarce, V., Johnson, D.C., Kaiser, M.F., Karadimitris, A,, Lam, E.W.F, Chevet, E., Feldhahn, N., Keun, H.C. and Auner, H.W.
Abstract

VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.

Year2019
JournalOncogene
Journal citation38, p. 3216–3231
PublisherSpringer Nature
ISSN0950-9232
Digital Object Identifier (DOI)https://doi.org/10.1038/s41388-018-0651-z
Publication dates
Print09 Jan 2019
Publication process dates
Accepted07 Dec 2018
Deposited17 Jun 2021
Publisher's version
License
File Access Level
Open
Permalink -

https://openresearch.lsbu.ac.uk/item/8wz47

  • 62
    total views
  • 34
    total downloads
  • 1
    views this month
  • 3
    downloads this month

Export as

Related outputs

MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis
Katsarou, A., Trasanidis, N., Ponnusamy, K., Kostopoulos, I., Alvarez-Benayas, J., Papaleonidopoulou, F., Keren, K., Sabbattini, P.M. R., Feldhahn, N., Papaioannou, M., Hatjiharissi, E., Sudbery, I., Chaidos, A., Caputo, V. and Karadimitris, A. (2023). MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis. Blood Advances. 7 (21), pp. 6395-6410. https://doi.org/10.1182/bloodadvances.2023009772
Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma
Trasanidis, N., Katsarou, A., Ponnusamy, K., Shen, Y.A., Kostopoulos, I.V., Bergonia, B., Keren, K., Reema, P., Xiao, X., Szydlo, R. M., Sabbattini, P., Roberts, I., Auner, H., Naresh, K., Chaidos, A., Wang, T.L., Magnani, L., Caputo, V. and Karadimitris, A. (2022). Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma. Blood. https://doi.org/10.1182/blood.2021014391
Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma
Alvarez-Benayas, J., Trasanidis, N., Katsarou, A., Ponnusamy, K., Chaidos, A., May, P.C., Xiao, X., Bua, M., Atta, M., Roberts, I., Auner, H.W., Hatjiharissi, E., Papaioannou, M., Caputo Galarce, V., Sudbery, I.M. and Karadimitris, A. (2021). Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma. Nature Communications. 12, p. 5450. https://doi.org/10.1038/s41467-021-25704-2
Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia
Iskander, D., Wang,G., Heuston, E.F., Christodoulidou, C., Psaila, B., Ponnusamy, K., Ren, H., Mokhtari, Z., Robinson, M., Chaidos, A., Trivedi, P., Trasanidis, N., Katsarou, A., Szydlo, R., NISC Comparative Sequencing Program, Palii, C.G., Ziadi, Z., Al-Oqaily, Q., Caputo Galarce, V., Roy, A., Harrington, Y., Karnik, L., Naresh, K., Mead,A.J., Thongjuea, S., Brand, M., de la Fuente, J., Bodine, D.M., Roberts,I. and Karadimitris, A. (2021). Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia. Science Translational Medicine. 13 (610). https://doi.org/10.1126/scitranslmed.abf0113
Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs
Saavedra-Garcia, P., Roman-Trufero, M., Al-Sadah, H.A., Blighe, K., Lopez-Jimenez, E., Christoforou, M., Penfold, L., Capece, D., Xiong, X., Miao, Y., Parzych, K., Caputo, V., Siskos, A.P., Encheva, V., Liu, Z., Thiel, D., Kaiser, M.F., Piazza, P., Chaidos, A., Karadimitris, A., Franzoso, G., Snijders, A.P., Keun, H.C., Oyarzun, D.A., Barahona, M. and Auner, H.W. (2021). Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs. PNAS. 118 (17), p. e2018229118. https://doi.org/10.1073/pnas.2018229118
The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma
Ponnusamy, K., Tzioni, M. M., Begum, M., Robinson, M. E., Caputo, V., Katsarou, A., Trasanidis, N., Xiao, X., Kostopoulos, I. V., Iskander, D., Roberts, I., Trivedi, P., Auner, H. W., Naresh, K., Chaidos, A. and Karadimitris, A. (2021). The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma. Haematologica. https://doi.org/10.3324/haematol.2020.274480
Role of Polymorphisms of NKG2D Receptor and Its Ligands in Acute Myeloid Leukemia and Human Stem Cell Transplantation
Machuldova, A., Holubova, M., Caputo, V.S., Cedikova, M., Jindra, P., Houdova, L. and Pitule, P. (2021). Role of Polymorphisms of NKG2D Receptor and Its Ligands in Acute Myeloid Leukemia and Human Stem Cell Transplantation. Frontiers in Immunology. 12, p. 651751. https://doi.org/10.3389/fimmu.2021.651751
Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro
Caputo Galarce, V., Trasanidis, N., Xiao, X., Robinson, M. E., Katsarou, A., Ponnusamy, K., Prinjha, R. K., Smithers, N., Chaidos, A., Auner, H. W. and Karadimitris, A. (2021). Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro. iScience. 24 (1), pp. 101989-101989. https://doi.org/10.1016/j.isci.2020.101989
Dynamic Changes of Inhibitory Killer-Immunoglobulin-Like Receptors on NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation: An Initial Study
Dekojová T., Houdová, L., Fatka, J., Pitule, P., Ostašov, P., Gmucová, H., Lysák, D., Jindra, P., Holubová, M. and Caputo Galarce, V. (2020). Dynamic Changes of Inhibitory Killer-Immunoglobulin-Like Receptors on NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation: An Initial Study. Journal of Clinical Medicine. 9 (11), p. 3502. https://doi.org/10.3390/jcm9113502
Evolution of Advanced Chronic Lymphoid Leukemia Unveiled by Single-Cell Transcriptomics: A Case Report
Ostasov, P., Robertson, H., Piazza, P., Datta, A., Apperley, J., Houdova, L., Lysak, D., Holubova, M., Tesarova, K., Caputo Galarce, V. and Barrozzi, I. (2020). Evolution of Advanced Chronic Lymphoid Leukemia Unveiled by Single-Cell Transcriptomics: A Case Report. Frontiers in Oncology. 10, p. 2356. https://doi.org/10.3389/fonc.2020.584607
Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells
Holubova, M., Leba, M., Gmucova, H., Caputo Galarce, V., Jindra, P. and Lysak, D. (2019). Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells. International Journal of Molecular Sciences. 20 (14), p. 3472. https://doi.org/10.3390/ijms20143472
Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting
Rotolo, A., Caputo Galarce, V., Holubova, M., Baxan, N., Dubois, O., Chaudhry, M.S., Xiao, X., Goudevenou, K., Pitcher, D.S., Petevi, K., Kachramanoglou, C., Iles, S., Naresh, K., Maher, J. and Karadimitris, A. (2018). Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting. Cancer Cell. 34 (4), pp. 596-610. https://doi.org/10.1016/j.ccell.2018.08.017
Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways
Psaila, B., Barkas, N., Iskander, D., Roy, A., Anderson, S., Ashley, N., Caputo Galarce, V., Lichtenberg, J., Loaiza, S., Bodine, D.M., Karadimitris, A., Mead, A.J. and Roberts, I. (2016). Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways. Genome Biology. 17 (1). https://doi.org/10.1186/s13059-016-0939-7