Reverse phase protein array identifies novel anti-invasion mechanisms of YC-1.
YC-1 has recently been demonstrated to have potent anti-invasion and anti-metastatic activity in several cancer models, in addition to its anti-proliferation activity. However, the mechanism underlying its anti-invasion/anti-metastatic activity is largely unknown. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer in Southeast Asia. Here, we demonstrated that YC-1 inhibited invasiveness and proliferation of NPC cells, with the latter being accompanied by PARP cleavage, S-phase arrest and activation of Chk1/Chk2. We aimed at identifying novel anti-invasion mechanisms of YC-1 in NPC by a functional proteomic platform, the reverse phase protein array (RPPA). Our study revealed for the first time that multiple invasion-related signaling proteins (beta-catenin, caveolin, Src and EGFR), as well as several growth-related proteins (AMPKalpha, phospho-acetyl-CoA carboxylase (p-ACC), HER-2 and mTOR), which were previously un-described signaling proteins altered by YC-1, were found to be down-modulated by YC-1 in NPC cells. We hypothesized that YC-1-mediated downregulation of these invasion proteins contributed to its anti-invasion activity in NPC cells. Overexpression of EGFR, activated Src or caveolin, but not beta-catenin reversed the inhibitory effects of YC-1 on NPC cell invasion, with EGFR and activated Src having additional effects on rescuing NPC cells from YC-1-mediated growth inhibition. In summary, we have identified several novel anti-invasion mechanisms of YC-1 that could impact NPC, and possibly other cancers as well.
Hong
Bo
B
Cancer Signaling Laboratory, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong.
Lui
Vivian W Y
VW
Hui
Edwin P
EP
Lu
Yiling
Y
Leung
Horasis S Y
HS
Wong
Elaine Y L
EY
Cheng
Suk-Hang
SH
Ng
Margaret H L
MH
Mills
Gordon B
GB
Chan
Anthony T C
AT
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D015536:Down-Regulation; D005663:Furans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D040081:Protein Array Analysis / Q000379:methods*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects
D000970:Antineoplastic Agents; D005663:Furans; D007191:Indazoles; D009363:Neoplasm Proteins; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases