| Literature DB >> 31969487 |
Xiaochao Tan1, Priyam Banerjee1, Edward A Pham2, Florentine U N Rutaganira3, Kaustabh Basu2, Neus Bota-Rabassedas1, Hou-Fu Guo1, Caitlin L Grzeskowiak4,5, Xin Liu1, Jiang Yu1, Lei Shi1, David H Peng1, B Leticia Rodriguez1, Jiaqi Zhang1, Veronica Zheng1, Dzifa Y Duose6, Luisa M Solis6, Barbara Mino6, Maria Gabriela Raso6, Carmen Behrens6, Ignacio I Wistuba6, Kenneth L Scott4,5, Mark Smith2,7, Khanh Nguyen2, Grace Lam2, Ingrid Choong2, Abhijit Mazumdar8, Jamal L Hill8, Don L Gibbons1, Powel H Brown8, William K Russell9, Kevan Shokat3, Chad J Creighton10,11, Jeffrey S Glenn12,13, Jonathan M Kurie14.
Abstract
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.Entities:
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Year: 2020 PMID： 31969487 PMCID： PMC7702266 DOI： 10.1126/scitranslmed.aax3772
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956