title: Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation.
abstract: Autophagy is closely related to tumor cell sensitivity to anticancer drugs. The HDAC (histone deacetylase) inhibitor valproic acid (VPA) interacted synergistically with chemotherapeutic agents to trigger lymphoma cell autophagy, which resulted from activation of AMPK (AMP-activated protein kinase) and inhibition of downstream MTOR (mechanistic target of rapamycin [serine/threonine kinase]) signaling. In an HDAC-independent manner, VPA potentiated the effect of doxorubicin on lymphoma cell autophagy via reduction of cellular inositol 1,4,5 trisphosphate (IP3), blockade of calcium into mitochondria and modulation of PRKAA1/2-MTOR cascade. In murine xenograft models established with subcutaneous injection of lymphoma cells, dual treatment of VPA and doxorubicin initiated IP3-mediated calcium depletion and PRKAA1/2 activation, induced in situ autophagy and efficiently retarded tumor growth. Aberrant genes involving mitochondrial calcium transfer were frequently observed in primary tumors of lymphoma patients. Collectively, these findings suggested an HDAC-independent chemosensitizing activity of VPA and provided an insight into the clinical application of targeting autophagy in the treatment of lymphoma.
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Ji
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.|b Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology ; Shanghai , China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: b Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology ; Shanghai , China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.|b Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology ; Shanghai , China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Peng-Peng
authors.initials: PP
authors.lastname: Xu
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.affiliation: b Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology ; Shanghai , China.|c U1165 Inserm/Université Paris 7; Hôpital Saint Louis ; Paris , France.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.
authors.forename: Shu
authors.initials: S
authors.lastname: Cheng
authors.affiliation: a State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine ; Shanghai , China.|b Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology ; Shanghai , China.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Zhao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014635:Valproic Acid; D015544:Inositol 1,4,5-Trisphosphate; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D020123:Sirolimus
keywords: AMP-activated; autophagy; catalytic subunit; chemosensitivity; histone deacetylase inhibitor; inositol 1,4,5 trisphosphate; lymphoma; protein kinase; valproic acid; α