RESUMO
Cancer cells harness lipid metabolism to promote their own survival. We screened 47 cancer cell lines for survival dependency on phosphatidylserine (PS) synthesis using a PS synthase 1 (PTDSS1) inhibitor and found that B cell lymphoma is highly dependent on PS. Inhibition of PTDSS1 in B cell lymphoma cells caused a reduction of PS and phosphatidylethanolamine levels and an increase of phosphoinositide levels. The resulting imbalance of the membrane phospholipidome lowered the activation threshold for B cell receptor (BCR), a B cell-specific survival mechanism. BCR hyperactivation led to aberrant elevation of downstream Ca2+ signaling and subsequent apoptotic cell death. In a mouse xenograft model, PTDSS1 inhibition efficiently suppressed tumor growth and prolonged survival. Our findings suggest that PS synthesis may be a critical vulnerability of malignant B cell lymphomas that can be targeted pharmacologically.
Assuntos
Linfoma de Células B , Fosfatidilserinas , Receptores de Antígenos de Linfócitos B , Animais , Humanos , Camundongos , Apoptose , Linfoma de Células B/genética , Fosfatidilserinas/biossíntese , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Fosfatidilinositóis , Transferases de Grupos Nitrogenados/antagonistas & inibidoresRESUMO
SIGNIFICANCE: This study identifies a specific dependency on PTDSS1 for phosphatidylserine synthesis following PTDSS2 deletion and introduces novel PTDSS1 inhibitors as a therapeutic option to induce collateral lethality in cancer with PTDSS2 loss.