SOX2 regulates apoptosis through MAP4K4-survivin signaling pathway in human lung cancer cells.
Previous studies have implicated cancer stem cells in tumor recurrence and revealed that the stem cell gene SOX2 plays an important role in the tumor cell resistance to apoptosis. Nonetheless, the mechanism by which SOX2 regulates apoptosis signals remained undefined. Here, we demonstrated the surprising finding that silencing of the SOX2 gene effectively induces apoptosis via the activation of death receptor and mitochondrial signaling pathways in human non-small cell lung cancer cells. Unexpectedly, reverse transcription-PCR analysis suggested that downregulation of SOX2 leads to activation of MAP4K4, previously implicated in cell survival. Evaluation of the apoptotic pathways revealed an increased expression of key inducers of apoptosis, including tumor necrosis factor-α and p53, with concurrent attenuation of Survivin. Although p53 appeared dispensable for this pathway, the loss of Survivin in SOX2-deficient cells appeared critical for the observed MAP4K4 induced cell death. Rescue experiments revealed that SOX2-silencing-mediated killing was blocked by ectopic expression of Survivin, or by reduction of MAP4K4 expression. Clinically, expressions of Survivin and SOX2 were highly correlated with each other. The results reveal a key target of SOX2 expression and highlight the unexpected context-dependent role for MAP4K4, a pluripotent activator of several mitogen-activated protein kinase pathways, in regulating tumor cell survival.
School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Si
S
Chen
Xuefei
X
Li
Dan
D
Lu
Yingxi
Y
Xu
Wenjun
W
Mou
Lina
L
Wang
Yanan
Y
Chen
Yanhua
Y
Liu
Xiru
X
Li
Lu-Yuan
LY
Li
Lin
L
Liu
Dwayne
D
Stupack
Ralph A
RA
Reisfeld
Rong
R
Xiang
Na
N
Li
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000502:physiology*; D000077022:Survivin
C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000077022:Survivin; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases