Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell death
Glioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)‐4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secr...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | FEBS Open Bio |
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| Online Access: | https://doi.org/10.1016/j.fob.2014.11.005 |
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| author | Jayashree C. Jagtap D. Parveen Reecha D. Shah Aarti Desai Dipali Bhosale Ashish Chugh Deepak Ranade Swapnil Karnik Bhushan Khedkar Aaishwarya Mathur Kumar Natesh Goparaju Chandrika Padma Shastry |
| author_facet | Jayashree C. Jagtap D. Parveen Reecha D. Shah Aarti Desai Dipali Bhosale Ashish Chugh Deepak Ranade Swapnil Karnik Bhushan Khedkar Aaishwarya Mathur Kumar Natesh Goparaju Chandrika Padma Shastry |
| author_sort | Jayashree C. Jagtap |
| collection | DOAJ |
| description | Glioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)‐4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secretory Par‐4 induces apoptosis in cancer cells, its potential in drug‐resistant tumors remains to be fully explored. Multicellular spheroids (MCS) of cancer cells often acquire multi‐drug resistance and serve as ideal experimental models. We investigated the role of Par‐4 in Tamoxifen (TAM)‐induced cell death in MCS of human cell lines and primary cultures of GBM tumors. TCGA and REMBRANT data analysis revealed that low levels of Par‐4 correlated with low survival period (21.85 ± 19.30 days) in GBM but not in astrocytomas (59.13 ± 47.26 days) and oligodendrogliomas (58.04 ± 59.80 days) suggesting low PAWR expression as a predictive risk factor in GBM. Consistently, MCS of human cell lines and primary cultures displayed low Par‐4 expression, high level of chemo‐resistance genes and were resistant to TAM‐induced cytotoxicity. In monolayer cells, TAM‐induced cytotoxicity was associated with enhanced expression of Par‐4 and was alleviated by silencing of Par‐4 using specific siRNA. TAM effectively induced secretory Par‐4 in conditioned medium (CM) of cells cultured as monolayer but not in MCS. Moreover, MCS were rendered sensitive to TAM‐induced cell death by exposure to conditioned medium (CM)‐containing Par‐4 (derived from TAM‐treated monolayer cells). Also TAM reduced the expression of Akt and PKCζ in GBM cells cultured as monolayer but not in MCS. Importantly, combination of TAM with inhibitors to PI3K inhibitor (LY294002) or PKCζ resulted in secretion of Par‐4 and cell death in MCS. Since membrane GRP78 is overexpressed in most cancer cells but not normal cells, and secretory Par‐4 induces apoptosis by binding to membrane GRP78, secretory Par‐4 is an attractive candidate for potentially overcoming therapy‐resistance not only in malignant glioma but in broad spectrum of cancers. |
| first_indexed | 2024-04-11T06:18:30Z |
| format | Article |
| id | doaj.art-65583f7157014eaa8040a23b7da11acf |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-04-11T06:18:30Z |
| publishDate | 2015-01-01 |
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| series | FEBS Open Bio |
| spelling | doaj.art-65583f7157014eaa8040a23b7da11acf2022-12-22T04:40:59ZengWileyFEBS Open Bio2211-54632015-01-015181910.1016/j.fob.2014.11.005Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell deathJayashree C. Jagtap0D. Parveen1Reecha D. Shah2Aarti Desai3Dipali Bhosale4Ashish Chugh5Deepak Ranade6Swapnil Karnik7Bhushan Khedkar8Aaishwarya Mathur9Kumar Natesh10Goparaju Chandrika11Padma Shastry12National Centre for Cell Science (NCCS), Pune, IndiaNational Centre for Cell Science (NCCS), Pune, IndiaNational Centre for Cell Science (NCCS), Pune, IndiaPersistent Systems Ltd., Pune, IndiaPersistent Systems Ltd., Pune, IndiaDepartment of Neurosurgery, Cimet's Inamdar Multispeciality Hospital, Pune, IndiaDepartment of Neurosurgery, D.Y. Patil Medical College, Pune, IndiaDepartment of Histopathology, Ruby Hall Clinic, Pune, IndiaDepartment of Histopathology, Ruby Hall Clinic, Pune, IndiaNational Centre for Cell Science (NCCS), Pune, IndiaNational Centre for Cell Science (NCCS), Pune, IndiaNational Centre for Cell Science (NCCS), Pune, IndiaNational Centre for Cell Science (NCCS), Pune, IndiaGlioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)‐4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secretory Par‐4 induces apoptosis in cancer cells, its potential in drug‐resistant tumors remains to be fully explored. Multicellular spheroids (MCS) of cancer cells often acquire multi‐drug resistance and serve as ideal experimental models. We investigated the role of Par‐4 in Tamoxifen (TAM)‐induced cell death in MCS of human cell lines and primary cultures of GBM tumors. TCGA and REMBRANT data analysis revealed that low levels of Par‐4 correlated with low survival period (21.85 ± 19.30 days) in GBM but not in astrocytomas (59.13 ± 47.26 days) and oligodendrogliomas (58.04 ± 59.80 days) suggesting low PAWR expression as a predictive risk factor in GBM. Consistently, MCS of human cell lines and primary cultures displayed low Par‐4 expression, high level of chemo‐resistance genes and were resistant to TAM‐induced cytotoxicity. In monolayer cells, TAM‐induced cytotoxicity was associated with enhanced expression of Par‐4 and was alleviated by silencing of Par‐4 using specific siRNA. TAM effectively induced secretory Par‐4 in conditioned medium (CM) of cells cultured as monolayer but not in MCS. Moreover, MCS were rendered sensitive to TAM‐induced cell death by exposure to conditioned medium (CM)‐containing Par‐4 (derived from TAM‐treated monolayer cells). Also TAM reduced the expression of Akt and PKCζ in GBM cells cultured as monolayer but not in MCS. Importantly, combination of TAM with inhibitors to PI3K inhibitor (LY294002) or PKCζ resulted in secretion of Par‐4 and cell death in MCS. Since membrane GRP78 is overexpressed in most cancer cells but not normal cells, and secretory Par‐4 induces apoptosis by binding to membrane GRP78, secretory Par‐4 is an attractive candidate for potentially overcoming therapy‐resistance not only in malignant glioma but in broad spectrum of cancers.https://doi.org/10.1016/j.fob.2014.11.005GlioblastomaPar-4Drug resistanceMulticellular spheroids (MCS)TamoxifenCytotoxicity |
| spellingShingle | Jayashree C. Jagtap D. Parveen Reecha D. Shah Aarti Desai Dipali Bhosale Ashish Chugh Deepak Ranade Swapnil Karnik Bhushan Khedkar Aaishwarya Mathur Kumar Natesh Goparaju Chandrika Padma Shastry Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell death FEBS Open Bio Glioblastoma Par-4 Drug resistance Multicellular spheroids (MCS) Tamoxifen Cytotoxicity |
| title | Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell death |
| title_full | Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell death |
| title_fullStr | Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell death |
| title_full_unstemmed | Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell death |
| title_short | Secretory prostate apoptosis response (Par)‐4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen‐induced cell death |
| title_sort | secretory prostate apoptosis response par 4 sensitizes multicellular spheroids mcs of glioblastoma multiforme cells to tamoxifen induced cell death |
| topic | Glioblastoma Par-4 Drug resistance Multicellular spheroids (MCS) Tamoxifen Cytotoxicity |
| url | https://doi.org/10.1016/j.fob.2014.11.005 |
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