Trerotola M.,Thomas Jefferson University |
Jernigan D.L.,Drexel University |
Liu Q.,Wistar Institute |
Siddiqui J.,Michigan Center for Translational Pathology |
And 4 more authors.
Cancer Research | Year: 2013
The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β1 integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on fibronectin, a phenomenon dependent on β1 integrins. Mechanistically, we demonstrate that Trop-2 and the α5β1 integrin associate through their extracellular domains, causing relocalization of α5β1 and the β1-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific as this molecule does not modulate migration on vitronectin, does not associate with the major vitronectin receptor, αvβ3 integrin, and does not affect localization of αvβ3 integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we show that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that β1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2. Cancer Res; 73(10); 3155-67. © 2013 AACR.
Mehra R.,University of Michigan |
Udager A.M.,University of Michigan |
Ahearn T.U.,Harvard University |
Cao X.,Michigan Center for Translational Pathology |
And 6 more authors.
European Urology | Year: 2015
The long noncoding RNA SChLAP1 is overexpressed in a subset of prostate cancers (PCa), and high SChLAP1 expression by in situ hybridization (ISH) independently predicts biochemical recurrence after radical prostatectomy. Importantly, although biochemical recurrence is a significant clinical outcome, it is not a validated surrogate for PCa-related mortality. Thus, we evaluated the association between SChLAP1 expression and development of lethal PCa in a large cohort of American men with PCa and long-term follow-up. SChLAP1 ISH was performed on tissue microarrays containing representative formalin-fixed, paraffin-embedded PCa tissue from all patients and scored using a semiquantitative method (ISH score range 0-400). Hazard ratios (HRs) for the association between SChLAP1 expression and time to development of lethal PCa were estimated using multivariable Cox regression analysis. Of the 937 patients evaluated, 89 (9.5%) had high SChLAP1 expression (ISH score ≥100), which in patients treated with radical prostatectomy was strongly associated with development of lethal PCa independent of age, Gleason score, pathologic stage, and PTEN status (HR 2.2, 95% confidence interval 1.1-4.1). These results suggest that SChLAP1 may be a useful tissue-based biomarker for identifying PCa patients at higher risk of lethal progression. Patient summary: We examined expression of the RNA molecule SChLAP1 in a large group of prostate cancer patients with long-term follow-up and found that patients with high SChLAP1 expression had a significantly higher chance of developing lethal disease. High SChLAP1 expression by ISH independently predicts lethal disease in a large cohort of American men with prostate cancer and long-term follow-up, suggesting that SChLAP1 ISH may be a promising biomarker for identifying patients at higher risk of lethal progression. © 2015 European Association of Urology.
Chakravarthi B.V.S.K.,Michigan Center for Translational Pathology |
Chakravarthi B.V.S.K.,University of Michigan |
Sujay R.,Indian Institute of Science |
Kuriakose G.C.,Indian Institute of Science |
And 2 more authors.
Cancer Cell International | Year: 2013
Background: Taxol (generic name paclitaxel), a plant-derived antineoplastic agent, used widely against breast, ovarian and lung cancer, was originally isolated from the bark of the Pacific yew, Taxus brevifolia. The limited supply of the drug has prompted efforts to find alternative sources, such as chemical synthesis, tissue and cell cultures of the Taxus species both of which are expensive and yield low levels. Fermentation processes with microorganisms would be the methods of choice to lower the costs and increase yields. Previously we have reported that F. solani isolated from T. celebica produced taxol and its precursor baccatin III in liquid grown cultures J Biosci 33:259-67, 2008. This study was performed to evaluate the inhibition of proliferation and induction of apoptosis of cancer cell lines by the fungal taxol and fungal baccatin III of F. solani isolated from T. celebica.Methods: Cell lines such as HeLa, HepG2, Jurkat, Ovcar3 and T47D were cultured individually and treated with fungal taxol, baccatin III with or without caspase inhibitors according to experimental requirements. Their efficacy on apoptotic induction was examined.Results: Both fungal taxol and baccatin III inhibited cell proliferation of a number of cancer cell lines with IC50 ranging from 0.005 to 0.2 μM for fungal taxol and 2 to 5 μM for fungal baccatin III. They also induced apoptosis in JR4-Jurkat cells with a possible involvement of anti-apoptotic Bcl2 and loss in mitochondrial membrane potential, and was unaffected by inhibitors of caspase-9,-2 or -3 but was prevented in presence of caspase-10 inhibitor. DNA fragmentation was also observed in cells treated with fungal taxol and baccatin III.Conclusions: The cytotoxic activity exhibited by fungal taxol and baccatin III involves the same mechanism, dependent on caspase-10 and membrane potential loss of mitochondria, with taxol having far greater cytotoxic potential. © 2013 Chakravarthi et al.; licensee BioMed Central Ltd.
McGregor N.,University of Michigan |
Patel L.,University of Michigan |
Craig M.,University of Michigan |
Weidner S.,University of Michigan |
And 3 more authors.
Journal of Cellular Biochemistry | Year: 2010
Prostate cancer remains a leading cause of cancer death in American men. Androgen deprivation therapy (ADT) is the most common treatment for advanced prostate cancer patients; however, ADT fails in nearly all cases resulting in castration resistant or androgen-insensitive (AI) disease. In many cases, this progression results from dysregulation of the pro-survival Bcl-2 family proteins. Inhibition of pro-survival Bcl-2 family proteins, therefore, may be an effective strategy to delay the onset of AI disease. Gossypol, a small molecule inhibitor of pro-survival Bcl-2 family proteins, has been demonstrated to inhibit AI prostate cancer growth. The apoptotic effect of gossypol, however, has been demonstrated to be attenuated by the presence of androgen in a prostate cancer xenograft mouse model (Vertebral Cancer of Prostate [VCaP]) treated with AT-101 (R-(-)-gossypol acetic acid). This study was undertaken to better understand the in vitro effects of androgen receptor (AR) on AT-101-induced apoptosis. VCaP cells treated with AT-101 demonstrated an increase in apoptosis and downregulation of Bcl-2 prosurvival proteins. Upon AR activation in combination with AT-101 treatment, apoptosis is reduced, cell survival increases, and caspase activation is attenuated. Akt and X inhibitor of apoptosis (XIAP) are downregulated in the presence of AT-101, and AR stimulation rescues protein expression. Combination treatment of bicalutamide and AT-101 increases apoptosis by reducing the expression of these pro-survival proteins. These data suggest that combination therapy of AT-101 and ADT may further delay the onset of AI disease, resulting in prolonged progression-free survival of prostate cancer patients. © 2010 Wiley-Liss, Inc.
Oh H.-K.,National University of Singapore |
Tan A.L.-K.,National University of Singapore |
Das K.,National University of Singapore |
Ooi C.-H.,National University of Singapore |
And 10 more authors.
Clinical Cancer Research | Year: 2011
Purpose: MicroRNAs (miRNA) play pivotal oncogenic and tumor-suppressor roles in several human cancers. We sought to discover novel tumor-suppressor miRNAs in gastric cancer (GC). Experimental Design: Using Agilent miRNA microarrays, we compared miRNA expression profiles of 40 primary gastric tumors and 40 gastric normal tissues, identifying miRNAs significantly downregulated in gastric tumors. Results: Among the top 80 miRNAs differentially expressed between gastric tumors and normals (false discovery rate < 0.01), we identified hsa-miR-486 (miR-486) as a significantly downregulated miRNA in primary GCs and GC cell lines. Restoration of miR-486 expression in GC cell lines (YCC3, SCH and AGS) caused suppression of several pro-oncogenic traits, whereas conversely inhibiting miR-486 expression in YCC6 GC cells enhanced cellular proliferation. Array-CGH analysis of 106 primary GCs revealed genomic loss of the miR-486 locus in approximately 25% to 30% of GCs, including two tumors with focal genomic losses specifically deleting miR-486, consistent with miR-486 playing a tumor-suppressive role. Bioinformatic analysis identified the secreted antiapoptotic glycoprotein OLFM4 as a potential miR-486 target. Restoring miR-486 expression in GC cells decreased endogenous OLFM4 transcript and protein levels, and also inhibited expression of luciferase reporters containing an OLFM4 3′ untranslated region with predicted miR-486 binding sites. Supporting the biological relevance of OLFM4 as a miR-486 target, proliferation in GC cells was also significantly reduced by OLFM4 silencing. Conclusions: miR-486 may function as a novel tumor-suppressor miRNA in GC. Its antioncogenic activity may involve the direct targeting and inhibition of OLFM4. ©2011 AACR.