Wei Ma, Karen Man-Fong Sze, Lo Kong Chan, Joyce Man-Fong Lee, Larry Lai Wei, Chun-Ming Wong, Terence Kin-Wah Lee, Carmen Chak-Lui Wong, Irene Oi-Lin Ng
Small Rho GTPase (Rho) and its immediate effector Rho kinase (ROCK) are reported to regulate cell survival, but the detailed molecular mechanism remains largely unknown. We had previously shown that Rho/ROCK signaling was highly activated in hepatocellular carcinoma (HCC). In this study, we further demonstrated that downregulation of RhoE, a RhoA antagonist, and upregulation of ROCK enhanced resistance to chemotherapy in HCC in both in vitro cell and in vivo murine xenograft models, whereas a ROCK inhibitor was able to profoundly sensitize HCC tumors to cisplatin treatment. Specifically, the ROCK2 isoform but not ROCK1 maintained the chemoresistance in HCC cells. Mechanistically, we demonstrated that activation of ROCK2 enhanced the phosphorylation of JAK2 and STAT3 through increased expression of IL-6 and the IL-6 receptor complex. We also identified IKKβ as the direct downstream target of Rho/ROCK, and activation of ROCK2 significantly augmented NF-κB transcription activity and induced IL-6 expression. These data indicate that Rho/ROCK signaling activates a positive feedback loop of IKKβ/NF-κB/IL-6/STAT3 which confers chemoresistance to HCC cells and is a potential molecular target for HCC therapy.
Hepatology. 2013 Jan;57(1):152-61
[PMID:
22829315]
Cancer Treat Rev. 2012 Nov;38(7):904-10
[PMID:
22651903]
Exp Cell Res. 2011 Aug 1;317(13):1787-95
[PMID:
21619876]
Cancer Cell. 2011 Aug 16;20(2):229-45
[PMID:
21840487]
Mol Cell Biol. 2003 Jun;23(12):4219-29
[PMID:
12773565]
Oncol Rep. 2012 Feb;27(2):573-8
[PMID:
22075557]
Nat Rev Cancer. 2009 Nov;9(11):798-809
[PMID:
19851315]
Curr Opin Cell Biol. 2008 Apr;20(2):242-8
[PMID:
18282695]
Cell Death Differ. 2012 May;19(5):735-42
[PMID:
22421963]
Cancer Res. 2012 Oct 1;72 (19):5025-34
[PMID:
22846914]
Hepatology. 2009 May;49(5):1583-94
[PMID:
19205033]
Oncogene. 2005 May 12;24(21):3397-408
[PMID:
15735721]
N Engl J Med. 2008 Jul 24;359(4):378-90
[PMID:
18650514]
Nat Protoc. 2012 Jan 05;7(1):171-92
[PMID:
22222791]
Nat Rev Gastroenterol Hepatol. 2010 Aug;7(8):448-58
[PMID:
20628345]
Cell Res. 2008 Feb;18(2):254-67
[PMID:
18227858]
Mol Hum Reprod. 2007 Mar;13(3):181-7
[PMID:
17227815]
Mol Cell Biol. 1990 May;10(5):2327-34
[PMID:
2183031]
Hepatology. 2001 Mar;33(3):577-81
[PMID:
11230737]
Sci Signal. 2013 Apr 02;6(269):pl1
[PMID:
23550210]
J Biol Chem. 2014 Jan 17;289(3):1429-40
[PMID:
24240172]
Nat Neurosci. 2012 Oct;15(10):1391-8
[PMID:
22941110]
Oncogene. 1999 Jan 7;18(1):47-57
[PMID:
9926919]
Cancer Biol Ther. 2012 Jan 1;13(1):25-33
[PMID:
22336585]
Blood Coagul Fibrinolysis. 2008 Oct;19(7):709-18
[PMID:
18832915]
J Biol Chem. 1997 Jun 6;272(23):15003-10
[PMID:
9169475]
J Neurosci Res. 2006 Feb 1;83(2):243-55
[PMID:
16385577]
Mol Biol Cell. 2001 Oct;12(10):3282-94
[PMID:
11598209]
Hepatology. 2012 Jun;55(6):1766-75
[PMID:
22234932]
Oncogene. 2008 Mar 13;27(12 ):1749-58
[PMID:
17891174]
J Cell Biol. 2006 Jul 17;174(2):277-88
[PMID:
16847103]
Mol Cancer Ther. 2007 Jun;6(6):1774-84
[PMID:
17575106]
Cancer Res. 2002 Jun 15;62(12):3387-94
[PMID:
12067980]
Biochim Biophys Acta. 2010 Apr;1805(2):167-80
[PMID:
20079806]
Animals
Carcinoma, Hepatocellular
Cell Line, Tumor
Cisplatin
Drug Resistance, Neoplasm
Drug Synergism
Humans
Interleukin-6
Liver Neoplasms
Male
Mice
Mice, Inbred BALB C
Mice, Nude
NF-kappa B
Protein Kinase Inhibitors
STAT3 Transcription Factor
Signal Transduction
Xenograft Model Antitumor Assays
rho GTP-Binding Proteins
rho-Associated Kinases
