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Cooperative roles of class 1A PI3K isoforms in cell survival and proliferation in translocation-related sarcoma

ABSTRACT: Among class 1 phosphatidylinositol 3-kinase (PI3K) isoforms, the isoform that predominantly regulates proliferation and survival in cancers dependent on PI3K signaling differs according to the genetic background and lineage of origin. We previously reported that translocation-related sarcomas (TRSs) including synovial sarcoma are highly susceptible to pan-class 1 PI3K inhibitors, but the dominant isoform remains unclear. In this study, we found that proliferation and survival in TRS cells were predominantly regulated by PI3Kα, with only minor contributions from PI3Kβ, PI3Kδ, and PI3Kγ. Interestingly, the combinatorial inhibition of PI3Kα, PI3Kβ, and PI3Kδ fully potentiate the antitumor activity and eventually induce apoptosis. To investigate the mechanism of the synergistic antitumor effects by the combinatorial inhibition, we performed global phosphoproteomic analysis of Aska-SS synovial sarcoma cell line treated with the PI3Kα-specific inhibitor alpelisib or the pan-PI3K inhibitor ZSTK474. We found that ZSTK474 inhibits Akt/mTOR signaling more strongly than alpelisib. Based on the results of phosphoproteomic analysis and subsequent validation experiments, we concluded that PI3Kα is the dominant isoform, while PI3Kβ and PI3Kδ can compensate for the function of PI3Kα and sustain the robustness of TRS cells in tumor proliferation and survival.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Sho Isoyama

PROVIDER: PXD062232 | JPOST Repository | Wed Mar 25 00:00:00 GMT 2026

REPOSITORIES: jPOST

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			Action	DRS
	220706_Lumos_Alp_60min.raw	Raw
	220706_Lumos_DMSO_60min.raw	Raw
	220706_Lumos_ZSTK_60min.raw	Raw
	220713_Lumos_Isoyama_LFQ_peptide_groups_for_JPOST.xlsx	Xlsx

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Cooperative roles of class 1A PI3K isoforms in cell survival and proliferation in translocation-related sarcoma

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