Invasive Prostate Carcinoma Driven by c-Src and Androgen Receptor Synergy

Cai, Houjian; Babić, Ivan; Wei, Xiao X.; Huang, Jiaoti; Witte, Owen N.

doi:10.1158/0008-5472.can-10-1605

Cited by 83 publications

(119 citation statements)

References 46 publications

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“…Our observation of SRC activity supports previous work that this kinase synergizes with other genes, including AR, to contribute to prostate adenocarcinoma (18,51). SRC has also been shown to interact with the intracellular region of ERBB2 (HER-2), supporting the notion that SRC may be an important node for targeted therapy in advanced prostate cancer (17,52).…”

Section: Discussionsupporting

confidence: 90%

“…The phosphorylation of PXN at Y 118 by focal adhesion kinase (FAK) increases cell motility and survival, which are characteristic features of cells that have undergone an epithelial-tomesenchymal transition (EMT) (38). The possibility of an EMT phenotype would be consistent with previous tumor phenotypes where SRC activation was observed (18). The manual curation of phosphotyrosine networks suggest novel associations of tyrosine kinase signaling with defined oncogenic insults in prostate cancer.…”

Section: Phosphoproteomic Profiling Identifies Oncogene-dependent Tyrmentioning

confidence: 68%

“…We demonstrate oncogene-specific signatures of global phosphotyrosine activity without ectopic expression of mutant tyrosine kinases in a mouse model of prostate cancer progression. The activation of tyrosine kinase signaling suggests the presence of alternative mechanisms regulating tyrosine kinase activity not related to activating mutations (18,21,22). These include but are not limited to loss of negative feedback mechanisms (e.g., increased or decreased phosphatase activity), transcriptional up-regulation of kinases, or increased stabilization of tyrosine kinases through decreased protein degradation (22,41,42).…”

Section: Discussionmentioning

confidence: 99%

“…In androgen-depleted conditions, tyrosine kinase, non-receptor, 2 (TNK2 or ACK1), SRC, and erythroblastic leukemia viral oncogene homolog 2 [ERBB2 (HER-2/neu)] tyrosine kinase activity can restore AR function in prostate cancer cells (14)(15)(16)(17). Increased expression of the tyrosine kinase SRC and AR can synergistically drive frank carcinoma of the mouse prostate (18). This relationship results in robust activation of SRC tyrosine kinase and MAPK signaling (18).…”

mentioning

confidence: 99%

“…Increased expression of the tyrosine kinase SRC and AR can synergistically drive frank carcinoma of the mouse prostate (18). This relationship results in robust activation of SRC tyrosine kinase and MAPK signaling (18). SRC activity was also observed in a subset of castration-resistant prostate cancer (CRPC) patients, which correlated with lower overall survival and increased metastatic disease (19).…”

mentioning

confidence: 99%

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Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

Drake

Graham²,

Stoyanova

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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148

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Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase signaling in advanced prostate cancer and identification of specific tyrosine kinase pathways from genetically defined tumor models point to unique therapeutic approaches using tyrosine kinase inhibitors for advanced prostate cancer.AKT | androgen receptor | ERG | K-RAS | bioinformatics

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Section: Discussionsupporting

confidence: 90%

Section: Phosphoproteomic Profiling Identifies Oncogene-dependent Tyrmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

Drake

Graham²,

Stoyanova

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

148

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Src controls castration recurrence of CWR22 prostate cancer xenografts

Gillard

Gao

et al. 2013

Cancer Medicine

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Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression.

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Src family kinases engage differential pathways for encapsulation into extracellular vesicles

Ye,

Gosser,

Runyon

et al. 2023

J of Extracellular Bio

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Extracellular vesicles (EVs) are heterogeneous biological nanoparticles secreted by all cell types. Identifying the proteins preferentially encapsulated in secreted EVs will help understand their heterogeneity. Src family kinases including Src and Fyn are a group of tyrosine kinases with fatty acylation modifications and/or multiple lysine residues (contributing charge interaction) at their N‐terminus. Here, we demonstrate that Src and Fyn kinases were preferentially encapsulated in EVs and fatty acylation including myristoylation and palmitoylation facilitated their encapsulation. Genetic loss or pharmacological inhibition of myristoylation suppressed Src and/or Fyn kinase levels in EVs. Similarly, loss of palmitoylation reduced Fyn levels in EVs. Additionally, mutation of lysine at sites 5, 7, and 9 of Src kinase also inhibited the encapsulation of myristoylated Src into EVs. Knockdown of TSG101, which is a protein involved in the endosomal sorting complexes required for transport (ESCRT) protein complex mediated EVs biogenesis and led to a reduction of Src levels in EVs. In contrast, filipin III treatment, which disturbed the lipid raft structure, reduced Fyn kinase levels, but not Src kinase levels in EVs. Finally, elevated levels of Src protein were detected in the serum EVs of host mice carrying constitutively active Src‐mediated prostate tumours in vivo. Collectively, the data suggest that different EVs biogenesis pathways exist and can regulate the encapsulation of specific proteins into EVs. This study provides an understanding of the EVs heterogeneity created by different EVs biogenesis pathways.

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Invasive Prostate Carcinoma Driven by c-Src and Androgen Receptor Synergy

Cited by 83 publications

References 46 publications

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

Src controls castration recurrence of CWR22 prostate cancer xenografts

Src family kinases engage differential pathways for encapsulation into extracellular vesicles

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