Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia.
Autophagy is a cellular adaptive mechanism to stress, including that induced by chemotherapeutic agents. Reverse phase protein array suggested that high expression of the essential autophagy-related protein, Atg7, was associated with shorter remission in newly diagnosed acute myeloid leukemia (AML) patient samples, indicating a role in chemoresistance. Knockdown of Atg7 in AML cells using short hairpin RNA markedly increased apoptosis and DNA damage following treatment with cytarabine and idarubicin. Interestingly, coculture of AML cells with stromal cells increased autophagy and chemoresistance in the AML cells exposed to chemotherapeutic agents, and this was reversed following Atg7 knockdown. This effect was further enhanced by concomitant knockdown of Atg7 in both AML and stromal cells. These findings strongly suggest that Atg7, and likely microenvironment autophagy in general, plays an important role in AML chemoresistance. Mechanistic studies revealed that Atg7 knockdown induced a proapoptotic phenotype in AML cells, which was manifested by an increased NOXA expression at the transcriptional level. Finally, in a mouse model of human leukemia, Atg7 knockdown extended overall survival after chemotherapy. Thus, the inhibition of Atg7 appears to be a valid strategy to enhance chemosensitivity, and it could indeed improve outcomes in AML therapy.
Department of Leukemia, Section of Molecular Hematology and Therapy, and.
Sujan
0000-0002-8976-540X
S
Piya
Department of Leukemia.
Steven M
0000-0002-5990-9548
SM
Kornblau
Department of Leukemia, Section of Molecular Hematology and Therapy, and.
Vivian R
0000-0003-4363-7258
VR
Ruvolo
Department of Leukemia, Section of Molecular Hematology and Therapy, and.
Hong
H
Mu
Department of Leukemia, Section of Molecular Hematology and Therapy, and.
Peter P
0000-0002-8574-1531
PP
Ruvolo
Department of Leukemia, Section of Molecular Hematology and Therapy, and.
Teresa
T
McQueen
Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.
R Eric
0000-0001-7311-0065
RE
Davis
Department of Leukemia.
Numsen
N
Hail
Department of Leukemia.
Hagop
H
Kantarjian
Department of Leukemia, Section of Molecular Hematology and Therapy, and.
Michael
M
Andreeff
Department of Leukemia, Section of Molecular Hematology and Therapy, and.
Gautam
0000-0001-7679-6453
G
Borthakur
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071193:Autophagy-Related Protein 7 / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7