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  • American Association for Cancer Research (AACR)  (5)
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  • American Association for Cancer Research (AACR)  (5)
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  • 1
    Online Resource
    Online Resource
    Abstract 3516: Tetrandrine promotes pancreatic cancer cell apoptosis in vitro and tumor regression in vivo
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3516-3516
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3516-3516
    Abstract: Introduction: Resistance to apoptosis is a hallmark of tumor progression and therapeutic failure in cancer, including Pancreatic Cancer. Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the United States with an overall five-year survival rate of less than five percent. The current standard treatment/s for PDAC are largely ineffective. There is an urgent yet unmet need for development of therapeutic agents for the treatment of PDAC. In the present study, we investigated the effects of Tetrandrine (a bis-benzylisoquinoline alkaloid) derivative- TET, on growth and viability of pancreatic cancer in vitro and in Xenograft models in vivo. Methods: Pancreatic Cancer cell lines: PANC-1 (epitheloid carcinoma), BxPC3 (Pancreatic Ductal Adeno-Carcinoma) and MiaPaCa2 (pancreatic carcinoma) were used in this study. Cytotoxicity was evaluated using the Crystal violet and MTT survival assays. Apoptosis was monitored by Flow cytometry following Annexin V/PI staining. Nuclear morphology was visualized by Immunofluorescence. Western Blot analysis was used to measure protein expression. Human pancreatic cancer (BXPC3) derived xenografts were generated in NOD/ SCID mice and TET (40 mg/kg body weight) was orally administered daily for four weeks. Tumor growth (measured as tumor volume by Vernier Caliper) and body weights were measured on alternate days. Tumor weight was measured at the end of the experimental period, prior to xenograft tissue harvesting. Results: TET inhibited growth and promoted cell death of pancreatic cancer cells in both dose and time dependent manner with an IC50 in the range of 5-10μM at 72 hr. The effects of TET were irreversible and there was progressive cell death with increasing time and at higher concentrations of TET. Treatment with TET resulted in nuclear condensation and apoptotic body formation, activation of caspase 3 and PARP cleavage, indicating apoptotic cell death. Moreover apoptosis was confirmed by flow cytometry after Annexin V and PI staining. TET administration not only halted the growth of BXPC3 derived xenografts, but also decreased tumor volume (TET treated vs PBS treated) over treatment period. Apoptosis (measured by TUNEL assay) was also observed in tumor tissues following TET treatment in vivo. Conclusion: These results show for the first time, that TET inhibits pancreatic cancer cell growth in vitro and induces pancreatic tumor regression in vivo in part by apoptosis. These results highlight the potential use of TET in treatment of pancreatic cancer. Acknowledgement: Financial support from following Sources is gratefully acknowledged: Carroll W. Feist endowed Chair Funds (Koul H), FWCC support and Chair commitment funds (Koul H) from the Chancellor and from the Dean School of Medicine- LSUHSC-Shreveport. All the members of Koul laboratory for their suggestions and help. Citation Format: Karnika Singh, Prakash Srinivasan Timiri Shanmugam, Sweaty Koul, Qin Dong, Neil Koul, Hari K. Koul. Tetrandrine promotes pancreatic cancer cell apoptosis in vitro and tumor regression in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3516.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3516
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
    Online Resource
    Online Resource
    Abstract 1079: PCDH7 is overexpressed in advanced prostate cancer and modulates aggressive phenotype in prostate cancer cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1079-1079
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1079-1079
    Abstract: Introduction: Most of prostate cancer (PCa) deaths are a result of distant metastasis and due to emergence of castrate resistant PCa (CRPC). Protocadherins (PCDHs) are members of the cadherin superfamily that regulate cell adhesion. Their extracellular domains contain cadherin-like repeats, but they differ significantly from classical cadherins with respect to their unique cytoplasmic domains that lack the conserved motifs for binding β-catenin and p120-catenin. PCDH7, a cadherin superfamily transmembrane protein that is known to function in cell-cell recognition and adhesion, is reported to be overexpressed in breast cancer and non-small cell lung cancer and promoted tumor metastasis. The role of PCDH7 in PCa is investigated for the first time in the present investigation. Materials and Methods: PCa cells- LNCaP, C4-2b, DU145, PC3, 22Rv1 and RWPE1 were used in this study. PCDH7 protein and mRNA levels were checked by Western Blotting and quantitative real time PCR respectively. Immunohistochemistry was done to check expression in TRAMP mice FFPE prostate tissue sections and human prostate tissues. Publically available data set (Trento 2016) was used to analyze PCDH7 expression in NEPC patients. PCDH7 lentiviral knock down was performed using PCDH7 shRNA in PC3 cells. Cell migration and invasion were done using IncuCyte® Scratch Wound Cell Migration and Invasion System. Colony formation was assessed by staining with 0.4% crystal violet after 3 weeks of cell seeding. Results: PCDH7 mRNA and protein is overexpressed in CRPC cells (C4-2b, 22Rv1, DU145 and PC3 cells as compared to castrations sensitive LNCaP cells as well as normal prostate RWPE1 cells. We observed highest levels for PCDH7 in enzalutamide refractory 22Rv1 cells. We also observed a significant increased expression of PCDH7 during tumor progression (30wk vs 12wk) in prostate tissues of TRAMP mice. Our results also show that PCDH7 is amplified in 9% of PCa patients and overexpressed in 43% patients. Immunohistochemical analysis of PCDH7 revealed high expression of PCDH7 in human prostate cancer tissues. EGF treatment enhanced ERK and AKT activities in time-dependent manner and the phosphorylation remain sustained even at late time points in PCDH7 positive PC3 cells as compared to decline in phosphorylation PCDH7 negative RWPE1 cells. shRNA-mediated knockdown of PCDH7 reduced ERK and AKT activities. Knockdown of PCDH7 also resulted in decreased cell migration, reduced cell invasion, and decreased colony formation. Collectively, these data suggest PCDH7 plays a crucial role in advanced PCa. Conclusion: Our results are the first direct demonstration of PCDH7 expression in PCa. Our exciting observations reveal a critical role for PCDH7 in prostate cancer progression. These results suggest that PCDH7 may be an attractive target for therapeutic intervention in PCa, in general, and CRPC in particular. Citation Format: Gauri Shishodia, Prakash Srinivasan Shanmugam, Sweaty Koul, Hari Koul. PCDH7 is overexpressed in advanced prostate cancer and modulates aggressive phenotype in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1079.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1079
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
    Online Resource
    Online Resource
    Abstract 4436: Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) is upregulated modulates prostate cancer growth and proliferation
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4436-4436
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4436-4436
    Abstract: Introduction: cap-dependent translation is necessary due to high protein requirement in cancer cells. An interaction between EIF4E and EIF4G is crucial for the formation of the EIF4F complex and initiation of cap-dependent translation. In the current study, we analyzed Human prostate cancer tissue microarray (TMA) and mRNA expression data in clinical datasets, and prostate tumor tissue from TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) model. We also assessed the functional role of EIF4G1 in commonly used PCa cell lines. Methods: Human prostate cancer tissue microarray was used to analyze the EIF4G1 level in patient samples. mRNA expression data for EIF4G1 was analyzed from TCGA and Trento/Cornell/Broad clinical data sets. PCa cells viz. LNCaP, C4-2b, 22Rv1, DU145, PC3 and normal human prostate cell line RWPE-1 were used. For an in-vivo model of PCa, we used TRAMP and wild-type mouse. Loss of function studies was performed by using siRNA/shRNA. Real-time PCR and Western Blot analysis were used to quantitate the relative mRNA and protein levels respectively. Analysis of polysome was performed by sucrose density gradient fractionation. Polysome-to-Monosome (P/M) ratios were determined for global translation activity. Cell cycle, cell proliferation, cell migration and Clonogenic activity were measured by standard methods. Results: Results from TMA analysis showed that protein levels of EIF4G1 are high in PCa as compared to normal prostate tissue, and there is a graded increase in EIF4G1 as the disease progresses. Results of our analysis of EIF4G1 expression in TCGA database revealed that increased expression of EIF4G1 positively correlated with higher tumor grade and stages (Gleason Score). Available data from Trento/Cornell/Broad clinical dataset revealed that 43% of castration-resistant prostate cancer (CRPC) patients have EIF4G1 mRNA up-regulation. PCa cells express a significantly higher level of EIF4G1 as compared to normal prostate cells. Similarly, prostate tumor tissue from TRAMP tissue showed higher EIF4G1 expression as compared to normal wild-type prostate tissue. Silencing of EIF4G1 causes G0/G1 cell cycle delay and decreases Cyclin D1 and p-Rb levels. There is a shift in polysome (P) to monosome (M) ratio with the siEIF4G1 knockdown in LNCaP and C4-2b. Loss of function studied by knockdown of EIF4G1 showed impaired Clonogenic activity as well as cell proliferation. Real-time PCR data suggests that EIF4G1 knockdown in LNCaP & C4-2b decreases the level of EMT markers such as N-Cadherin, Vimentin & Zeb1 and limits the cell migration in C4-2b cells. Conclusions: Taken all together, our data indicate that EIF4G1 may function as an oncoprotein and is a novel target for intervention in PCa and CRPC. Citation Format: Praveen K. Jaiswal, Sweaty Koul, Prakash Srinivasan Timiri Shanmugam, Hari K. Koul. Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) is upregulated modulates prostate cancer growth and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4436.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-4436
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
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    Online Resource
    Abstract 5061: TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5061-5061
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5061-5061
    Abstract: Introduction: Prostate cancer (PCa) is the 2nd most common malignancy in USA. Novel agents for treatment of advanced PCa are warranted. Transgenic adenocarcinoma of the mouse prostate (TRAMP) is an autochthonous mouse model exhibits both histological and morphological features that mimic human prostate carcinogenesis. Herein, for the first time, we evaluated the in vivo effects of TET, a derivative of Tetrandrine in TRAMP model. Methods: Beginning 12 weeks of age, male TRAMP mice were administrated with TET (30 mgm/kg body weight, orally, alternative days) in PBS or PBS alone (Control) till 30 weeks of age. Body weight (B) of animals was recorded weekly. At various time points animals were euthanized, genitourinary tract (G) were weighed. Prostate tissue was subjected to immunohistochemical analyses for SV40-TAg, epithelial-mesenchymal transition (EMT), proliferation, neuroendocrine differentiation (NED) and apoptosis. Multiple organs were examined for drug toxicity and lungs were analyzed for metastasis. Results: TRAMP mice exhibit to high-grade prostatic intraepithelial neoplasia (PIN) by 12 weeks and progresses to poorly differentiated adeno-carcinoma by 30 weeks with distant metastasis to lungs. TET feeding did not show any considerable difference body weight loss profiles during the entire treatment regimen. At the time of necropsy, there was no evidence of edema, abnormal organ size or appearance in non-target organs. TET gavage group showed (p & lt;0.005) lower G/B ratio compared to the PBS treated group. These findings clearly indicate that TET dosing is non-toxic and restricts the abnormal growth of the prostate in TRAMP mice. TET repress the EMT as well as NED transition and inhibits cell proliferation (p & lt;0.005) by Ki-67 staining. Oral administration of TET inhibits PCa growth and progression by increases (p & lt;0.005) apoptosis in tumor tissues. Further, TET inhibited metastasis as there was significant (p & lt;0.005) decrease in metastasis to lungs in TET treated animals. Conclusion: Human achievable dose of TET treatment to TRAMP mice bearing prostate tumor, exhibited no-observed-adverse-effect-level in toxicology evaluations and also significantly inhibited tumor growth, progression, local invasion and distant metastasis involving suppression of tumor, and thus could have potential against human PCa. Citation Format: Hari K. Koul, Prakash Srinivasan Timiri Shanmugam, Praveen K. Jaiswal, Sweaty Koul. TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5061. doi:10.1158/1538-7445.AM2017-5061
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5061
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 5
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    Online Resource
    Abstract 3525: PDEF promote prostate cancer luminal/epithelial differentiation and inhibit tumor progression
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3525-3525
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3525-3525
    Abstract: Conventional therapies produce a high rate of cure for patients with localized prostate cancer (PCa), but there is no effective treatment for castration resistant metastatic PCa. Transcription factors by association with enhancer and super-enhancer elements are key drivers of cell identity. Our previous studies have shown that Sam Pointed Domain Ets Transcription Factor a.k.a. Prostate Derived Ets Factor (SPDEF/PDEF), inhibits cell migration, invasion and clonogenic activity in PCa cells and there is a graded loss of PDEF with increasing Gleason Score in PCa patient samples. PDEF has been reported to be one of the cell identity transcription factors in LNCaP cells. We proposed that PDEF functions as a putative tumor metastasis suppressor. Others have shown an increase in Twist1, a bHLH transcription factor, was positively correlated with Gleason Grading. Present study was designed to investigate the role of PDEF and interplay between PDEF and Twist1 in PCa. PC3 cells were stably transfected with PDEF/control PABABE vectors. Gene expression changes were monitored by Affymetrix microarray. Microarray was analyzed with GSEA. qRT-PCR was performed to confirm gene expression and IHC, IF and IB analysis were performed to visualize protein expression. Chip-seq data (SRP002475) was aligned with Bowtie. Peaks were identified by MACS and visualized using IGB. PDEF/Twist1 expression data was extracted from GSE16560. GraphPad was used to generate KM survival analysis of PCa patients. Our results show that PDEF expression is limited to epithelial/luminal cells of the prostatic glands. We observed that expression of Twist1 was down regulated in PC3 cells following PDEF expression. Analysis of gene expression data from our microarray studies revealed that PDEF re-expression was associated with negative enrichment of gene sets involved with cell migration and positive enriched of gene sets involved with epithelial/luminal differentiation. Chip-seq analysis revealed a binding of PDEF to KRT8/18 promoter region. These data suggest that PDEF inhibits core metastasis related genes through promoting a program of luminal/epithelial differentiation. In clinical samples of PCa, expression of PDEF was inversely associated, while expression of Twist1 was positively associated with Gleason grade. PDEF and Twist1 was able to predict patient survival, moreover integrated PDEF and Twist1 expression was able to better predict PCa patient survival as compared to PDEF or Twist1 alone. PDEF inhibits cell migration and metastasis in part by down-regulating Twist1 level and promoting luminal/epithelial differentiation. Loss of PDEF combined with gain of Twist1 expression may serve as a potential biomarker set for distinguishing lethal PCa from an indolent disease. Additional studies are underway to gain further insights into the role of PDEF in PCa progression and metastasis. Acknowledgement: FWCC support and Chair commitment funds (Koul H). Citation Format: Fengtian Wang, Sweaty Koul, Prakash Srinivasan Timiri Shanmugam, Qin Dong, Hari K. Koul. PDEF promote prostate cancer luminal/epithelial differentiation and inhibit tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3525. doi:10.1158/1538-7445.AM2017-3525
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3525
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
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