Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors
Abstract Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kin...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-02-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05690-7 |
| _version_ | 1797863389282697216 |
|---|---|
| author | Sho Isoyama Naomi Tamaki Yutaka Noguchi Mutsumi Okamura Yuki Yoshimatsu Tadashi Kondo Takeshi Suzuki Shin-ichi Yaguchi Shingo Dan |
| author_facet | Sho Isoyama Naomi Tamaki Yutaka Noguchi Mutsumi Okamura Yuki Yoshimatsu Tadashi Kondo Takeshi Suzuki Shin-ichi Yaguchi Shingo Dan |
| author_sort | Sho Isoyama |
| collection | DOAJ |
| description | Abstract Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing’s sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients. |
| first_indexed | 2024-04-09T22:34:47Z |
| format | Article |
| id | doaj.art-449aec3bd3674ec2a73c663ca55309a8 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T22:34:47Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-449aec3bd3674ec2a73c663ca55309a82023-03-22T12:32:15ZengNature Publishing GroupCell Death and Disease2041-48892023-02-0114211010.1038/s41419-023-05690-7Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitorsSho Isoyama0Naomi Tamaki1Yutaka Noguchi2Mutsumi Okamura3Yuki Yoshimatsu4Tadashi Kondo5Takeshi Suzuki6Shin-ichi Yaguchi7Shingo Dan8Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDivision of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDivision of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDivision of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDepartment of Patient-derived Cancer Model, Tochigi Cancer CenterDivision of Rare Cancer Research, National Cancer Center Research InstituteDivision of Functional Genomics, Cancer Research Institute, Kanazawa UniversityDivision of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDivision of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchAbstract Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing’s sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.https://doi.org/10.1038/s41419-023-05690-7 |
| spellingShingle | Sho Isoyama Naomi Tamaki Yutaka Noguchi Mutsumi Okamura Yuki Yoshimatsu Tadashi Kondo Takeshi Suzuki Shin-ichi Yaguchi Shingo Dan Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors Cell Death and Disease |
| title | Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors |
| title_full | Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors |
| title_fullStr | Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors |
| title_full_unstemmed | Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors |
| title_short | Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors |
| title_sort | subtype selective induction of apoptosis in translocation related sarcoma cells induced by puma and bim upon treatment with pan pi3k inhibitors |
| url | https://doi.org/10.1038/s41419-023-05690-7 |
| work_keys_str_mv | AT shoisoyama subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT naomitamaki subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT yutakanoguchi subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT mutsumiokamura subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT yukiyoshimatsu subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT tadashikondo subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT takeshisuzuki subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT shinichiyaguchi subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors AT shingodan subtypeselectiveinductionofapoptosisintranslocationrelatedsarcomacellsinducedbypumaandbimupontreatmentwithpanpi3kinhibitors |