Submitted on March 31, 2005
Accepted on November 1, 2005
Cell Proliferation and Drug Resistance in Hepatocellular Carcinoma are modulated by Rho GTPase Signals
Sterpetti Paola1*, Marucci Luca1, Candelaresi Cinzia1, Toksoz Deniz2, Alpini Gianfranco3, Ugili Laura1, Svegliati Baroni Gianluca1, Macarri Giampiero1, and Benedetti Antonio1
1 Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy
2 Department of Physiology, Tufts University School of Medicine, Boston, MA, USA
3 Department of Internal Medicine and Medical Physiology, The Texas A&M University System HSC, COM and Central Texas Veterans HCS, Temple, TX, USA
* To whom correspondence should be addressed. E-mail: clingastro{at}mta01.univpm.it.
Hepatocellular carcinoma is highly resistant to chemotherapeutic agents, thus, the need to discover effective therapeutic molecules to suppress cancer cell growth and to overcome drug-resistance is urgent. The Rho-GTPase is implicated in cancer and metastasis, and is activated by LBC (for Lymphoid-Blast-Crisis) Rho-guanine-nucleotide-exchange-factor. The aim of the study is to analyze the expression of Lbc in hepatocarcinoma and to determine the effect of LBC expression on growth rate and resistance to genotoxic stress.
We showed by immunohistochemistry and northern blot, that Lbc is absent in normal adult liver and abundantly expressed in hepatocarcinoma, implying an increased Rho pathway signalling. Lbc stably transfected hepatocarcinoma cells, exhibit increased proliferation and levels of ERK and cyclin D1 activation which are blocked by a Rho inhibitor. Furthermore, Lbc expression confers increased resistance to genotoxic stress induced by doxorubicin which is associated to upregulation of Bcl-2 and BAD phosphorylation and is reversed by a Rho inhibitor.
In conclusion these data support a role for Rho in liver cancer progression and resistance to therapy, and may provide a basis for developing effective treatment for hepatocarcinoma.
