RSK Promotes Prostate Cancer Progression in Bone through ING3, CKAP2, and PTK6-Mediated Cell Survival

Yu, Guoyu; Lee, Yu Chen; Cheng, Chien Jui; Wu, Cong; Song, Jian; Gallick, Gary E.; Yu-Lee, Li-Yuan; Kuang, Jian; Lin, Sue Hwa

doi:10.1158/1541-7786.mcr-14-0384-t

Cited by 45 publications

(34 citation statements)

References 36 publications

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“…We also observed that the fraction of proteins overlapping with any of the “hallmark” gene sets to be higher when including the phosphoproteomic data, accounting for any potential study bias. These results provide evidence of actionable phosphorylation events in metastatic CRPC, several of which have previously been implicated in this disease including PRKDC, PRKAA2, and AKT (Goodwin et al, 2015; Yu et al, 2015) (Park et al, 2009) while others such as RPS6KA4 and MCM2 represent new drug targets.…”

Section: Resultsmentioning

confidence: 58%

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer

Drake

Paull

Graham

et al. 2016

Cell

209

234

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SUMMARY We used clinical tissue from lethal metastatic castration resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that sheds light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.

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Section: Resultsmentioning

confidence: 58%

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer

Drake

Paull

Graham

et al. 2016

Cell

209

234

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“…RSKs function downstream of MEK, ERK and protein kinase C, and are frequently activated in various types of cancer, including leukemia, and this activation may be triggered by steroids, insulin, epidermal growth factor and estrogen. Previous studies have demonstrated that RSK1 is overexpressed in prostate (28), breast (29) and colon cancer tissues (30).…”

Section: A B Discussionmentioning

confidence: 99%

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Deng

Jiang

et al. 2017

Oncology Letters

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Abstract. Ribosomal S6 kinases (RSKs) are directly regulated by extracellular signal-regulated kinase (ERK) signaling and are implicated in cell growth, survival, motility and senescence. The present study observed that RSK1 was overexpressed in primary untreated leukemia patient bone marrow samples compared with the expression at the complete remission stage, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a high RSK1 expression (relative expression ≥10) was associated with a significantly shorter overall survival (P=0.038) compared with that in patients with low RSK1 expression (relative expression <10). The current study also investigated the effect of luteolin, a novel p90 ribosomal S6 kinase (RSK) inhibitor extracted from Reseda odorata L., which shows strong biochemical functions including anti-allergy, anti-inflammation and anti-cancer functions, in MOLM-13 and Kasumi-1 leukemic cells. The cell viability, apoptosis and migration ability analysis were assessed by performing a cell counting kit-8 assay, Annexin V-FITC/PI double staining and migration filter assay, respectively. The results indicated that luteolin inhibited the growth of the leukemic cell lines through induction of apoptosis, while the migration ability was also suppressed. Overexpression of RSK1 by plasmid transfection was found to decrease the luteolin-induced apoptosis and migration capabilities. By contrast, knockdown of the RSK1 expression by small interfering RNA appeared to induce the same effect as luteolin on MOLM-13 and Kasumi-1 leukemic cells. In conclusion, these results suggest that luteolin inhibits leukemic cell proliferation and induces apoptosis by inhibition of the RSK1 pathways. IntroductionRibosomal S6 kinases (RSKs) are a family of serine/threonine protein kinases that are directly regulated by extracellular signal-regulated kinase (ERK) signaling. RSK1, a member of the RSK family, was initially identified as an X-linked gene in patients with mental retardation (1-3). Typically, RSK is expressed in the cerebellum during embryogenesis and silenced postnatally. Aberrant RSK signaling is integral for various types of cancer, including breast, colon and renal cancer, as well as melanoma. Li et al (4) observed that the p90 RSK2-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells. Degen et al (5) also demonstrated this phenomenon, and further observed that overexpression of RSK3 and RSK1 supports cellular proliferation under the PI3K signaling pathway blockade. This occurs through the inhibition of apoptosis and regulation of cellular translation in squamous carcinoma cell through phosphorylation of RSK and eukaryotic translation initiation factor 4B. It is thus reported that RSK1 serves a role in squamous carcinoma cell growth and proliferation. In addition, Cohen et al (6) observed that RSK1 overexpression is associated with sunitinib resistance in renal cell carcinoma cell lines. Elf et al (7) also reported that, altho...

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“…The Rsk2 inhibitor SL0101-1 was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). A constitutively active (CA) RSK2 construct (35) was provided by Dr. Sue-Hwa Lin (MD Anderson, Houston, TX). Three human breast cancer cell lines were used in these studies.…”

Section: Methodsmentioning

confidence: 99%

Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

Mao

Summers

Xiang

et al. 2016

Molecular Cancer Research

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The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the anti-metastatic actions of melatonin have not been well established. In the present study, the anti-metastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phosphorylation-dependent activation of numerous kinases and transcription factors that drive drug resistance and metastasis in breast cancer. A key signaling node activated by the Her2/Mapk/Erk pathway is Rsk2, which has been shown to induce numerous signaling pathways associated with the development of epithelial-to-mesenchymal transition (EMT) and metastasis including: Creb, Stat3, cSrc, Fak, Pax, Fascin, and actin polymerization. The data demonstrate that melatonin (both endogenous and exogenous) significantly represses this invasive/metastatic phenotype through a mechanism that involves the suppression of EMT, either by promoting mesenchymal-to-epithelial transition (MET), and/or by inhibiting key signaling pathways involved in later stages of metastasis. These data, combined with our earlier in vitro studies, support the concept that maintenance of elevated and extended duration of nocturnal melatonin levels plays a critical role in repressing the metastatic progression of breast cancer.

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RSK Promotes Prostate Cancer Progression in Bone through ING3, CKAP2, and PTK6-Mediated Cell Survival

Cited by 45 publications

References 36 publications

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

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