المؤلفون: Sanjeev Kumar, Derek B. Oien, Ashwani Khurana, William Cliby, Lynn Hartmann, Jeremy Chien, Viji Shridhar

المصدر: Frontiers in Oncology, Vol 9 (2019)

مصطلحات موضوعية: CC2D1A, Freud1, ovarian cancer, prognostic marker, chemotherapy resistance, treatment-refractory tumor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Recurrence within 6 months of the last round of chemotherapy is clinically defined as platinum-resistant ovarian cancer. Gene expression associated with early recurrence may provide insights into platinum resistant recurrence. Prior studies identified a 14-gene model that accurately predicted early or late recurrence in 86% of patients. One of the genes identified was CC2D1A (encoding coiled-coil and C2 domain containing 1A), which showed higher expression in tumors from patients with early recurrence. Here, we show that CC2D1A protein expression was higher in cisplatin-resistant ovarian cancer cell lines compared to cisplatin-sensitive cell lines. In addition, immunohistochemical analysis of patient tumors on a tissue microarray (n = 146) showed that high levels of CC2D1A were associated with a significantly worse overall and progression-free survival (p = 0.0002 and p = 0.006, respectively). To understand the contribution of CC2D1A in chemoresistance, we generated shRNA-mediated knockdown of CC2D1A in SKOV3ip and PEO4 cell lines. Cell death and clonogenic assays of these isogenic clonal lines clearly showed that downregulation of CC2D1A resulted in increased sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Moreover, nude mice bearing SKOV3ip xenografts with stably downregulated CC2D1A were more sensitive to chemotherapy as evidenced by a significantly longer survival time compared to xenografts derived from cells stably transduced with non-targeting shRNA. These results suggest CC2D1A promotes chemotherapy resistance in ovarian cancer.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fonc.2019.00986/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/4e356caf18644a2986e5b17c2e0bc124Test

المؤلفون: Prabhu Thirusangu, Christopher L. Pathoulas, Upasana Ray, Yinan Xiao, Julie Staub, Ling Jin, Ashwani Khurana, Viji Shridhar

المصدر: Cancers, Vol 13, Iss 9, p 2004 (2021)

مصطلحات موضوعية: quinacrine, autophagy, CTSL, LMP, MOMP, ovarian cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting QC-induced autophagic flux and apoptotic cell death in OC cells. Using a Magic Red® cathepsin L activity assay and LysoTracker red, we discerned that QC-induced CTSL activation promotes lysosomal membrane permeability (LMP) resulting in the release of active CTSL into the cytosol to promote apoptotic cell death. We found that QC-induced LMP and CTSL activation promotes Bid cleavage, mitochondrial outer membrane permeabilization (MOMP), and mitochondrial cytochrome-c release. Genetic (shRNA) and pharmacological (Z-FY(tBU)-DMK) inhibition of CTSL markedly reduces QC-induced autophagy, LMP, MOMP, apoptosis, and cell death; whereas induced overexpression of CTSL in ovarian cancer cell lines has an opposite effect. Using recombinant CTSL, we identified p62/SQSTM1 as a novel substrate of CTSL, suggesting that CTSL promotes QC-induced autophagic flux. CTSL activation is specific to QC-induced autophagy since no CTSL activation is seen in ATG5 knockout cells or with the anti-malarial autophagy-inhibiting drug chloroquine. Importantly, we showed that upregulation of CTSL in QC-treated HeyA8MDR xenografts corresponds with attenuation of p62, upregulation of LC3BII, cytochrome-c, tBid, cleaved PARP, and caspase3. Taken together, the data suggest that QC-induced autophagy and CTSL upregulation promote a positive feedback loop leading to excessive autophagic flux, LMP, and MOMP to promote QC-induced cell death in ovarian cancer cells.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/13/9/2004Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/29e385f4fc1f41ab8ac36862db2e3b8cTest

المؤلفون: Viji Shridhar, Alfonso Baldi, Jeremy Chien, Wilma Lingle, Robert J. Linhardt, Bo Yang, Kaustubh Datta, Bruno Vincenzi, Laura Lorenzon, Pasquale Mellone, Peng Liu, Ashwani Khurana

الوصف: Supplementary Materials and Methods. Figure S1: Quantitative Real-time PCR. Figure S2: MCF7 cells were transfected with HIF-1α siRNA oligos and control siRNA oligos before exposing them to hypoxia (3% oxygen) for indicated time intervals. Figure S3 : MTT assay was performed on MCF10DCIS batch clones after 24 hours of treatments as indicated. Figure S4: (A and B) pcDNA3.1 or pcDNA3.1 HSulf-1-myc/His plasmid transfected MCF10DCIS. Figure S5: K means cluster analysis of HSulf-1 expression with hypoxia signature genes as described in supplementary materials and methods. Figure S6: Kaplan-Meier survival analysis was performed to evaluate HSulf-1 mRNA expression levels with disease-free and overall patient survival. Figure S7: Proposed model. Table S1: Primers used for cloning, ChIP and siRNA oligos. Table S2: Patient Characteristics. Table S3: Chi-square statistical analysis of HSulf-1 and CAIX expression. Table S4: Prognostic factors in breast cancer cases compared with disease-free survival. Table S5: Prognostic factors in breast cancer cases compared with overall survival. Table S6: Characteristics of clinical parameters of breast cancer and HSulf-1 mRNA.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::80052fa63119d2f5334c4718f08b198bTest
https://doi.org/10.1158/0008-5472.22390554.v1Test

المؤلفون: Viji Shridhar, Alfonso Baldi, Jeremy Chien, Wilma Lingle, Robert J. Linhardt, Bo Yang, Kaustubh Datta, Bruno Vincenzi, Laura Lorenzon, Pasquale Mellone, Peng Liu, Ashwani Khurana

الوصف: HSulf-1 modulates the sulfation states of heparan sulfate proteoglycans critical for heparin binding growth factor signaling. In the present study, we show that HSulf-1 is transcriptionally deregulated under hypoxia in breast cancer cell lines. Knockdown of HIF-1α rescued HSulf-1 downregulation imposed by hypoxia, both at the RNA and protein levels. Chromatin immunoprecipitation with HIF-1α and HIF-2α antibodies confirmed recruitment of HIF-α proteins to the two functional hypoxia-responsive elements on the native HSulf-1 promoter. HSulf-1 depletion in breast cancer cells resulted in an increased and sustained bFGF2 (basic fibroblast growth factor) signaling and promoted cell migration and invasion under hypoxic conditions. In addition, FGFR2 (fibroblast growth factor receptor 2) depletion in HSulf-1–silenced breast cancer cells attenuated hypoxia-mediated cell invasion. Immunohistochemical analysis of 53 invasive ductal carcinomas and their autologous metastatic lesions revealed an inverse correlation for the expression of HSulf-1 to CAIX in both the primary tumors (P ≥ 0.0198) and metastatic lesions (P ≥ 0.0067), respectively, by χ2 test. Finally, HSulf-1 expression levels in breast tumors by RNA in situ hybridization showed that high HSulf-1 expression is associated with increased disease-free and overall survival (P ≥ 0.03 and P ≥ 0.0001, respectively). Collectively, these results reveal an important link between loss of HSulf-1 under hypoxic microenvironment and increased growth factor signaling, cell migration, and invasion. Cancer Res; 71(6); 2152–61. ©2011 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::b5a82f9a9b827faa3bbe1f093eb5cc30Test
https://doi.org/10.1158/0008-5472.c.6502983.v1Test

المؤلفون: Viji Shridhar, Blake Gilks, Sean Dowdy, Steve Kalloger, Xiaoping He, Ramandeep Rattan, Ashwani Khurana, Peng Liu

الوصف: Supplementary Figure 1 from Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2fa29740a6cc2cb73714d2d75368ba6eTest
https://doi.org/10.1158/0008-5472.22377915.v1Test

المؤلفون: Viji Shridhar, Blake Gilks, Sean Dowdy, Steve Kalloger, Xiaoping He, Ramandeep Rattan, Ashwani Khurana, Peng Liu

الوصف: Supplementary Table 1 from Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::39d8754838049d36f060b16dc4f92ff6Test
https://doi.org/10.1158/0008-5472.22377903Test

المؤلفون: Viji Shridhar, Blake Gilks, Sean Dowdy, Steve Kalloger, Xiaoping He, Ramandeep Rattan, Ashwani Khurana, Peng Liu

الوصف: Supplementary Methods from Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6948f292b093c5a8b2024dbb7a43fc60Test
https://doi.org/10.1158/0008-5472.22377906Test

المؤلفون: Viji Shridhar, Blake Gilks, Sean Dowdy, Steve Kalloger, Xiaoping He, Ramandeep Rattan, Ashwani Khurana, Peng Liu

الوصف: Supplementary Figure Legends 1-2 from Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::093844d3e1878fc6619a174dbf4f4340Test
https://doi.org/10.1158/0008-5472.22377909.v1Test

المؤلفون: Viji Shridhar, Blake Gilks, Sean Dowdy, Steve Kalloger, Xiaoping He, Ramandeep Rattan, Ashwani Khurana, Peng Liu

الوصف: Supplementary Table 2 from Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2b5414e70241f016d770084ce93f4cd9Test
https://doi.org/10.1158/0008-5472.22377900Test

المؤلفون: Viji Shridhar, Blake Gilks, Sean Dowdy, Steve Kalloger, Xiaoping He, Ramandeep Rattan, Ashwani Khurana, Peng Liu

الوصف: Supplementary Figure 2 from Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ba0fab97f9c7a0b6a2cfc5a9d2b22be0Test
https://doi.org/10.1158/0008-5472.22377912.v1Test