Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma
Multiple myeloma grows by establishing multiple interactions with bone marrow cells. These include expansion of myeloid-derived suppressor cells, which drive immunoevasion via mechanisms that include arginase-1-driven depletion of L-arginine, thus indirectly promoting myeloma cell survival and tumor...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.968208/full |
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| author | Matteo Trudu Matteo Trudu Laura Oliva Ugo Orfanelli Alessandra Romano Alessandra Romano Francesco Di Raimondo Francesca Sanvito Maurilio Ponzoni Maurilio Ponzoni Simone Cenci Simone Cenci |
| author_facet | Matteo Trudu Matteo Trudu Laura Oliva Ugo Orfanelli Alessandra Romano Alessandra Romano Francesco Di Raimondo Francesca Sanvito Maurilio Ponzoni Maurilio Ponzoni Simone Cenci Simone Cenci |
| author_sort | Matteo Trudu |
| collection | DOAJ |
| description | Multiple myeloma grows by establishing multiple interactions with bone marrow cells. These include expansion of myeloid-derived suppressor cells, which drive immunoevasion via mechanisms that include arginase-1-driven depletion of L-arginine, thus indirectly promoting myeloma cell survival and tumor progression. The peculiar biology of malignant plasma cells postulates that arginine depletion may benefit their fitness also directly, e.g., by engaging the integrated stress response, or by stimulating autophagy through mTORC1 inhibition. We thus investigated the direct impact of arginine deprivation on myeloma cells and challenged its pathophysiological relevance in vitro and in vivo. First, we found that partial arginine depletion spared proliferation of human multiple myeloma cells at concentrations that arrest human T cells. Next, we asked if arginine shortage activates putative adaptive pathways in myeloma cells. Low arginine failed to activate the integrated stress response, as indicated by unmodified phosphorylation of the eukaryotic initiation factor 2α, but sizably inhibited mTORC1, as revealed by reduced phosphorylation of ribosomal protein S6. Notably, depressed mTORC1 activity was not sufficient to increase autophagy, as assessed by the lysosomal digestion rate of the autophagosome-associated protein, LC3-II. Rather, it stimulated mTORC2, resulting in increased phosphatidylinositol-3 kinase-dependent AKT phosphorylation and activity, leading to heightened inhibitory phosphorylation of the pro-apoptotic BAD protein. We then tested whether arginine depletion-activated AKT may protect malignant plasma cells from cell death. Indeed, culturing myeloma cells in low arginine medium significantly reduced the apoptotic effect of the first-in-class proteasome inhibitor, bortezomib, an outcome prevented by pharmacological inhibition of AKT phosphorylation. Finally, we challenged the relevance of the identified circuit in vivo. To gauge the pathophysiologic relevance of low arginine to myeloma growth independently of immunoevasion, we xenotransplanted human myeloma cells subcutaneously into T cell-deficient Rag2–/–γc–/– recipient mice and treated palpable tumor-bearing mice with the clinical-grade arginase inhibitor CB1158. Arginase inhibition significantly raised serum arginine concentration, reduced tumor growth by caliper assessment, and decreased intra-tumor AKT phosphorylation in vivo. Altogether, our results reveal a novel direct pro-survival effect of arginine deprivation on myeloma cells, with potential therapeutic implications. |
| first_indexed | 2024-04-12T22:55:13Z |
| format | Article |
| id | doaj.art-ee9ee6a946354a0890f7b365ec56d587 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T22:55:13Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-ee9ee6a946354a0890f7b365ec56d5872022-12-22T03:13:13ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-09-011210.3389/fonc.2022.968208968208Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myelomaMatteo Trudu0Matteo Trudu1Laura Oliva2Ugo Orfanelli3Alessandra Romano4Alessandra Romano5Francesco Di Raimondo6Francesca Sanvito7Maurilio Ponzoni8Maurilio Ponzoni9Simone Cenci10Simone Cenci11Age Related Diseases, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, ItalyUniversity Vita-Salute San Raffaele, Milano, ItalyAge Related Diseases, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, ItalyAge Related Diseases, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, ItalyAge Related Diseases, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, ItalyDepartment of Surgery and Medical Specialties, University of Catania, Catania, ItalyDepartment of Surgery and Medical Specialties, University of Catania, Catania, ItalyPathology Unit, San Raffaele Scientific Institute, Milano, ItalyUniversity Vita-Salute San Raffaele, Milano, ItalyPathology Unit, San Raffaele Scientific Institute, Milano, ItalyAge Related Diseases, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, ItalyUniversity Vita-Salute San Raffaele, Milano, ItalyMultiple myeloma grows by establishing multiple interactions with bone marrow cells. These include expansion of myeloid-derived suppressor cells, which drive immunoevasion via mechanisms that include arginase-1-driven depletion of L-arginine, thus indirectly promoting myeloma cell survival and tumor progression. The peculiar biology of malignant plasma cells postulates that arginine depletion may benefit their fitness also directly, e.g., by engaging the integrated stress response, or by stimulating autophagy through mTORC1 inhibition. We thus investigated the direct impact of arginine deprivation on myeloma cells and challenged its pathophysiological relevance in vitro and in vivo. First, we found that partial arginine depletion spared proliferation of human multiple myeloma cells at concentrations that arrest human T cells. Next, we asked if arginine shortage activates putative adaptive pathways in myeloma cells. Low arginine failed to activate the integrated stress response, as indicated by unmodified phosphorylation of the eukaryotic initiation factor 2α, but sizably inhibited mTORC1, as revealed by reduced phosphorylation of ribosomal protein S6. Notably, depressed mTORC1 activity was not sufficient to increase autophagy, as assessed by the lysosomal digestion rate of the autophagosome-associated protein, LC3-II. Rather, it stimulated mTORC2, resulting in increased phosphatidylinositol-3 kinase-dependent AKT phosphorylation and activity, leading to heightened inhibitory phosphorylation of the pro-apoptotic BAD protein. We then tested whether arginine depletion-activated AKT may protect malignant plasma cells from cell death. Indeed, culturing myeloma cells in low arginine medium significantly reduced the apoptotic effect of the first-in-class proteasome inhibitor, bortezomib, an outcome prevented by pharmacological inhibition of AKT phosphorylation. Finally, we challenged the relevance of the identified circuit in vivo. To gauge the pathophysiologic relevance of low arginine to myeloma growth independently of immunoevasion, we xenotransplanted human myeloma cells subcutaneously into T cell-deficient Rag2–/–γc–/– recipient mice and treated palpable tumor-bearing mice with the clinical-grade arginase inhibitor CB1158. Arginase inhibition significantly raised serum arginine concentration, reduced tumor growth by caliper assessment, and decreased intra-tumor AKT phosphorylation in vivo. Altogether, our results reveal a novel direct pro-survival effect of arginine deprivation on myeloma cells, with potential therapeutic implications.https://www.frontiersin.org/articles/10.3389/fonc.2022.968208/fullAKTarginineautophagymammalian target of rapamycinmultiple myelomaplasma cell |
| spellingShingle | Matteo Trudu Matteo Trudu Laura Oliva Ugo Orfanelli Alessandra Romano Alessandra Romano Francesco Di Raimondo Francesca Sanvito Maurilio Ponzoni Maurilio Ponzoni Simone Cenci Simone Cenci Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma Frontiers in Oncology AKT arginine autophagy mammalian target of rapamycin multiple myeloma plasma cell |
| title | Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma |
| title_full | Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma |
| title_fullStr | Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma |
| title_full_unstemmed | Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma |
| title_short | Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma |
| title_sort | preclinical evidence of a direct pro survival role of arginine deprivation in multiple myeloma |
| topic | AKT arginine autophagy mammalian target of rapamycin multiple myeloma plasma cell |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.968208/full |
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