{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:39:45Z","timestamp":1793817585038,"version":"4.6.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>PI3K\/AKT signaling pathway is upregulated in a broad spectrum of cancers. Among the class I PI3Ks (PI3K\u03b4\/\u03b2\/\u03b4 isoforms), PI3K\u03b4 has been implicated in hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence has highlighted the involvement of aberrant mRNA splicing in cancer development\/progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Our previous studies revealed that <jats:italic>PIK3CD-S<\/jats:italic> is an oncogenic splice variant that promotes tumor aggressiveness and drug resistance in prostate cancer (PCa). To further evaluate the potential of utilizing PI3K\u03b4-S (encoded from <jats:italic>PIK3CD-S<\/jats:italic>) as a cancer biomarker and\/or drug target, comprehensive analyses were performed in a series of patient samples and cell lines derived from endocrine\/solid tumors. Specifically, IHC, immunofluorescence, western blot and RT-PCR assay results have demonstrated that PI3K\u03b4 isoforms were highly expressed in endocrine\/solid tumor patient specimens and cell lines.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Differential <jats:italic>PIK3CD-S\/PIK3CD-L<\/jats:italic> expression profiles were identified in a panel of endocrine\/solid tumor cells. SiRNA knockdown of <jats:italic>PIK3CD-L<\/jats:italic> or <jats:italic>PIK3CD-S<\/jats:italic> differentially inhibits AKT\/mTOR signaling in PCa, breast, colon and lung cancer cell lines. Moreover, siRNA knockdown of <jats:italic>PTEN<\/jats:italic> increased PI3K\u03b4 levels and activated AKT\/mTOR signaling, while overexpression of <jats:italic>PTEN<\/jats:italic> reduced PI3K\u03b4 levels and inhibited AKT\/mTOR signaling in cancer cells. Intriguingly, PI3K\u03b4-S levels remained unchanged upon either siRNA knockdown or overexpression of PTEN. Taken together, these results suggested that PTEN negatively regulates PI3K\u03b4-L and its downstream AKT\/mTOR signaling, while PI3K\u03b4-S promotes AKT\/mTOR signaling without regulation by PTEN. Lastly, PI3K\u03b4 inhibitor Idelalisib and SRPK1\/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3K\u03b4-expressing endocrine\/solid tumors. Our results have shown that Idelalisib effectively inhibited PI3K\u03b4-L (but not PI3K\u03b4-S) mediated AKT\/mTOR signaling. In contrast, SRPIN340 reversed the aberrant mRNA splicing, thereby inhibiting AKT\/mTOR signaling. <jats:italic>In-vitro<\/jats:italic> functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities\/growths of tumor spheroids) in inhibiting the advanced tumor cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In summary, our study has suggested a promising potential of utilizing PI3K\u03b4-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1190479","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T15:38:59Z","timestamp":1692632339000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Aberrant 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