| CCR9 mediates PI3K/AKT-dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9-CCL25 interaction enhances the cytotoxic effects of etoposide. | |
| | |
MedLine Citation:
|
PMID: 20127861 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Despite recent advances in treatment and management of prostate cancer (PCa), it remains the second leading cause of cancer-related deaths among men in the US. Chemotherapy is one of the treatment alternatives for hormone refractory metastatic PCa. However, current chemotherapeutic regimens provide palliative benefit but relatively modest survival advantage primarily due to chemo-resistance and upregulated antiapoptotic machineries in PCa cells. Therefore, blocking the mechanisms responsible for suppression of apoptosis might improve current chemotherapeutic regimens. In this study, we show that CC chemokine receptor-9 (CCR9) and its natural ligand CCL25 interaction upregulates antiapoptotic proteins (i.e., PI3K, AKT, ERK1/2 and GSK-3beta) and downregulate activation of caspase-3 in PCa cells. Significant downregulation of these CCR9-mediated antiapoptotic proteins in the presence of a PI3K inhibitor (wortmannin), further suggests that the antiapoptotic action of CCR9 is primarily regulated through PI3K. Furthermore, the cytotoxic effect of etoposide was significantly inhibited in the presence of CCL25, and this inhibitory effect of CCL25 was abrogated when CCR9-CCL25 interaction was blocked using anti-CCR9 monoclonal antibodies. In conformation to these in vitro studies, significant reduction in tumor burden was found in mice receiving CCL25 neutralizing antibodies and etoposide together as compared to both as a single agent. These results suggest that the CCR9-CCL25 axis mediates PI3K/AKT-dependent antiapoptotic signals in PCa cells and could be a possible reason for low apoptosis and modest chemotherapeutic response. Therefore, targeting CCR9-CCL25 axis with cytotoxic agents may provide better therapeutic outcomes than using cytotoxic agents alone. |
| | |
Authors:
|
Praveen K Sharma; Rajesh Singh; Kristian R Novakovic; John W Eaton; William E Grizzle; Shailesh Singh |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: International journal of cancer. Journal international du cancer Volume: 127 ISSN: 1097-0215 ISO Abbreviation: Int. J. Cancer Publication Date: 2010 Nov |
Date Detail:
|
Created Date: 2010-09-02 Completed Date: 2010-09-15 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
|
Languages: eng Pagination: 2020-30 Citation Subset: IM |
Affiliation:
|
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
1-Phosphatidylinositol 3-Kinase
/
metabolism* Animals Antineoplastic Agents / pharmacology* Apoptosis* Caspase 3 / biosynthesis Cell Line, Tumor Chemokines, CC / metabolism* Disease Progression Enzyme Activation Etoposide / pharmacology* Humans Male Mice Mice, Nude Prostatic Neoplasms / drug therapy*, metabolism* Proto-Oncogene Proteins c-akt / metabolism* Receptors, CCR / metabolism* Signal Transduction |
| Chemical | |
Reg. No./Substance:
|
0/Antineoplastic Agents; 0/CC chemokine receptor 9; 0/CCL25 protein, human; 0/Chemokines, CC; 0/Receptors, CCR; 33419-42-0/Etoposide; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Intra-epithelial p63-dependent expression of distinct components of cell adhesion complexes in norma...
Next Document: Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma models: Definin...