Abstract
BackgroundAlthough major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefore, the identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Activation of small GTPases such as Ras and Arf1 is a critical component of the signaling pathways for most of the receptors shown to be upregulated in advanced prostate cancer.MethodsThe drug effects on cell proliferation were measured by CellTiter 96® AQueous One Solution Cell Proliferation Assay. The drug effects on cell migration and invasion were determined by Radius™ 24-well and Matrigel-coated Boyden chambers. The drug effects on apoptosis were assessed by FITC Annexin V Apoptosis Detection Kit with 7-AAD and Western blot with antibodies against cleaved PARP and Caspase 3. A NOD/SCID mouse model generated by subcutaneous injection was used to assess the in vivo drug efficacy in tumor growth. ERK activation and tumor cell proliferation in xenografts were examined by immunohistochemistry.ResultsWe show that Exo2, a small-molecule inhibitor that reduces Arf1 activation, effectively suppresses prostate cancer cell proliferation by blocking ERK1/2 activation. Exo2 also has other effects, inhibiting migration and invasion of PCa cells and inducing apoptosis. The Ras inhibitor salirasib augments Exo2-induced cytotoxicity in prostate cancer cells partially by enhancing the suppression of ERK1/2 phosphorylation. In a xenograft mouse model of prostate cancer, Exo2 reduces prostate tumor burden and inhibits ERK1/2 activation at a dose of 20 mg/kg. Synergistic treatment of salirasib and Exo2 exhibits a superior inhibitory effect on prostate tumor growth compared with either drug alone, which may be attributed to the more efficient inhibition of ERK1/2 phosphorylation.ConclusionThis study suggests that simultaneous blockade of Arf1 and Ras activation in prostate cancer cells is a potential targeted therapeutic strategy for preventing prostate cancer development.
Highlights
Major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents
Exo2 inactivates ERK1/2 signaling and inhibits proliferation in prostate cancer cells Loss of Arf1 leads to reduced phosphorylation levels of ERK1/2 (25)
The decreased GTP-bound Arf1 was positively associated with reduced ERK1/2 activation (Fig. 1e). These data indicate that Exo2-induced repression of proliferation in prostate cancer cells, at least partially, through inhibiting the Arf1-ERK1/2 signaling cascade
Summary
Major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. The identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Various treatment options for prostate cancer, including hormone deprivation and chemotherapy, largely depend on the severity of disease, functional status, age and genetic. Chemotherapies are often used to treat prostate cancer that is resistant to hormone ablation therapy. A good example for chemotherapeutic treatment is docetaxel with prednisone, which has been shown to be effective in regression of metastatic hormone refractory Prostate cancer [5]. The identification of new central molecular targets in cancer progression and development of new targeted therapies or improved treatment regimens are very necessary for achieving better survival for patients with prostate cancer
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