Details

Autor(en) / Beteiligte

• Tan, Xiaochao
• Banerjee, Priyam
• Pham, Edward A
• Rutaganira, Florentine U N
• Basu, Kaustabh
• Bota-Rabassedas, Neus
• Guo, Hou-Fu
• Grzeskowiak, Caitlin L
• Liu, Xin
• Yu, Jiang
• Shi, Lei
• Peng, David H
• Rodriguez, B Leticia
• Zhang, Jiaqi
• Zheng, Veronica
• Duose, Dzifa Y
• Solis, Luisa M
• Mino, Barbara
• Raso, Maria Gabriela
• Behrens, Carmen
• Wistuba, Ignacio I
• Scott, Kenneth L
• Smith, Mark
• Nguyen, Khanh
• Lam, Grace
• Choong, Ingrid
• Mazumdar, Abhijit
• Hill, Jamal L
• Gibbons, Don L
• Brown, Powel H
• Russell, William K
• Shokat, Kevan
• Creighton, Chad J
• Glenn, Jeffrey S
• Kurie, Jonathan M

Titel

PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma

Ist Teil von

• Science translational medicine, 2020-01, Vol.12 (527)

Ort / Verlag

United States

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.