Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia.
Understanding the complexity and dynamics of cancer cells in response to effective therapy requires hypothesis-driven, quantitative, and high-throughput measurement of genes and proteins at both spatial and temporal levels. This study was designed to gain insights into molecular networks underlying the clinical synergy between retinoic acid (RA) and arsenic trioxide (ATO) in acute promyelocytic leukemia (APL), which results in a high-quality disease-free survival in most patients after consolidation with conventional chemotherapy. We have applied an approach integrating cDNA microarray, 2D gel electrophoresis with MS, and methods of computational biology to study the effects on APL cell line NB4 treated with RA, ATO, and the combination of the two agents and collected in a time series. Numerous features were revealed that indicated the coordinated regulation of molecular networks from various aspects of granulocytic differentiation and apoptosis at the transcriptome and proteome levels. These features include an array of transcription factors and cofactors, activation of calcium signaling, stimulation of the IFN pathway, activation of the proteasome system, degradation of the PML-RARalpha oncoprotein, restoration of the nuclear body, cell-cycle arrest, and gain of apoptotic potential. Hence, this investigation has provided not only a detailed understanding of the combined therapeutic effects of RA/ATO in APL but also a road map to approach hematopoietic malignancies at the systems level.
Zheng
Pei-Zheng
PZ
State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Second Medical University, 197 Rui Jin Road II, Shanghai 200025, China.
Wang
Kan-Kan
KK
Zhang
Qun-Ye
QY
Huang
Qiu-Hua
QH
Du
Yan-Zhi
YZ
Zhang
Qing-Hua
QH
Xiao
Da-Kai
DK
Shen
Shu-Hong
SH
Imbeaud
Sandrine
S
Eveno
Eric
E
Zhao
Chun-Jun
CJ
Chen
Yu-Long
YL
Fan
Hui-Yong
HY
Waxman
Samuel
S
Auffray
Charles
C
Jin
Gang
G
Chen
Sai-Juan
SJ
Chen
Zhu
Z
Zhang
Ji
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D004357:Drug Synergism; D015180:Electrophoresis, Gel, Two-Dimensional; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D010087:Oxides / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049490:Systems Biology / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide