Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells.
OBJECTIVE
Aberrant activation of Ras and Raf in mitogen-activated protein kinase (MAPK) signaling has been linked with cancer. However, the role of MAPK kinases (MAPKKs or MEKs) in cancer is unclear, although constitutively activated MEK1, which does not exist in nature, is "oncogenic." Herein, we found that T-cell-originated protein kinase (TOPK), a member of the MAPKK protein family, is highly expressed in human colorectal cancer tissues and cell lines and plays an important role in the transformation of colorectal cancer.


METHODS
The biologic consequences of overexpression or knockdown of TOPK in JB6 Cl41 and HCT116 colorectal cancer cells were studied in vitro and in vivo, respectively. Kinase assay or transient transfection experiments were performed to study the bidirectional signaling pathway between TOPK and extracellular signal-regulated kinase (ERK).


RESULTS
TOPK was shown to promote transformation in vitro and in vivo, and knockdown of TOPK in HCT116 colorectal cancer cells reduced this cell lines' tumorigenic properties in vitro and in vivo. Furthermore, a positive feedback loop between TOPK and ERK2 was identified. With epidermal growth factor treatment, knockdown of either TOPK or ERK2 in HCT116 cells resulted in a decreased phosphorylation of ERK2 or TOPK, respectively, and knockdown of TOPK in HCT116 colorectal cancer cells blocked the phosphorylation of downstream substrates of ERK2.


CONCLUSIONS
The positive feedback loop between TOPK and ERK2 increases tumorigenesis properties of HCT116 colorectal cancer cells, and TOPK-regulated signaling may serve as a potential therapeutic target in colorectal cancer.
Zhu
Feng
F
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Zykova
Tatyana A
TA
Kang
Bong Seok
BS
Wang
Zhe
Z
Ebeling
Mara C
MC
Abe
Yasuhito
Y
Ma
Wei-Ya
WY
Bode
Ann M
AM
Dong
Zigang
Z
D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase