Lactotransferrin acts as a tumor suppressor in nasopharyngeal carcinoma by repressing AKT through multiple mechanisms.
LTF (lactotransferrin, also known as lactoferrin) is a key component of innate immune defense. It has recently been found to have anti-tumor and anti-metastatic activity in different cancers. We previously reported LTF to be the most significantly downregulated gene in nasopharyngeal carcinoma (NPC) specimens relative to normal nasopharyngeal epithelial tissues, and it was also negatively associated with the progression and metastasis of NPC. However, the mechanism underlying this remains unclear. In the current study, we revealed that LTF can suppress 3-phosphoinositide-dependent protein kinase 1 expression via the mitogen-activated protein kinase/c-Jun pathway and thus repress AKT signaling. We also showed that LTF interacts with keratin 18 (K18) and so blocks the formation of the K18-14-3-3 complex, leading to downregulation of K18-mediated AKT activation. Thus, LTF suppresses AKT signaling by two separate mechanisms, leading to inhibition of NPC tumorigenesis. This is the first report on the tumor suppressive effects of LTF through repression of AKT signaling in NPC. It suggests that both LTF and AKT signaling merit further study in the field of NPC research.
Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
M
M
Deng
W
W
Zhang
H
H
Tang
Q
Q
Ye
Q
Q
Liao
Y
Y
Zhou
M
M
Wu
W
W
Xiong
Y
Y
Zheng
X
X
Guo
Z
Z
Qin
W
W
He
M
M
Zhou
J
J
Xiang
X
X
Li
J
J
Ma
G
G
Li
D048948:14-3-3 Proteins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005092:Exonucleases / Q000378:metabolism; D005095:Exoribonucleases; D005260:Female; D015870:Gene Expression; D006801:Humans; D007781:Lactoferrin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D007781:Lactoferrin