Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.
In: Journal of Clinical Investigation, Jg. 134 (2024-06-17), Heft 12, S. 1-17
academicJournal
Zugriff:
Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway Ca2+ transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate Ca2+-dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintained intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiated the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibited the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupted prosurvival autocrine loops and attenuated prometastatic processes in the tumor microenvironment. As it potentially underlies the selective activity of Mn against 3q-amplified malignancies, ATP2C1 coamplification increased Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between coamplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies. [ABSTRACT FROM AUTHOR]
Titel: |
Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.
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Autor/in / Beteiligte Person: | Tan, Xiaochao ; Wang, Shike ; Xiao, Guan-Yu ; Wu, Chao ; Liu, Xin ; Zhou, Biyao ; Jiang, Yu ; Duose, Dzifa Y. ; Xi, Yuanxin ; Wang, Jing ; Gupta, Kunika ; Pataer, Apar ; Roth, Jack A. ; Kim, Michael P. ; Chen, Fengju ; Creighton, Chad J. ; Russell, William K. ; Kurie, Jonathan M. |
Zeitschrift: | Journal of Clinical Investigation, Jg. 134 (2024-06-17), Heft 12, S. 1-17 |
Veröffentlichung: | 2024 |
Medientyp: | academicJournal |
ISSN: | 0021-9738 (print) |
DOI: | 10.1172/JCI176355 |
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