Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

Yeh, Chen Yun; Shin, Shin Mei; Yeh, Hsuan‐Hsien; Wu, Tsung Jung; Shin, Jyh Wei; Chang, Tsuey Yu; Raghavaraju, Giri; Lee, Chung Ta; Chiang, Jung-Hsien; Tseng, Vincent S.; Lee, Yuan Chii G.; Shen, Cheng; Chow, Nan Haw; Liu, Hsiao Sheng

doi:10.1186/1471-2407-11-139

Cited by 67 publications

(64 citation statements)

References 44 publications

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“…2A) revealing signaling cross-talk within the MPNSTs between MET and the PDGF and IL receptors (PDGF-R and ILR, respectively). This is in concordance with previous studies identifying crosstalk between receptor tyrosine kinases and MET in cancer cell lines (22,23). We show that HGF-induced wound healing in the ST8814, S1844.1, and S1507.2 cells was significantly reduced after inhibition of MET with both the SU11274 and PF-4217903 inhibitors (Fig.…”

Section: Resultssupporting

confidence: 93%

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Rad

Dodd

Thomas

et al. 2015

Molecular Cancer Research

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Therapeutic options are limited for neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoral molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signaling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1, and S1507.2) were used. The data demonstrate that small-molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration, and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion, and tumor formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3 functions as a common driver of tumorigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of hypoxiainducible factor (HIF)1a, HIF2a, and VEGF-A in all four MPNST lines. Finally, the data demonstrate that wound healing, cell migration, invasion, and tumor formation through STAT3 are highly dependent on HIF signaling, where knockdown of HIF1a ablated these oncogenic facets of STAT3.Implications: This research reveals that aberrant STAT3 and HIF1a activity drives tumor progression in MPNSTs, indicating that inhibition of the STAT3/HIF1a/VEGF-A signaling axis is a viable treatment strategy.

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Section: Resultssupporting

confidence: 93%

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Rad

Dodd

Thomas

et al. 2015

Molecular Cancer Research

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“…As Fra-1 controls tumour cell motility and proliferation and is widely expressed in cells of bladder tumours, molecular pathways upstream or downstream of Fra-1 represent attractive potential therapeutic targets. In a recent study, IHC analysis of AXL expression has been reported in T 2 -T 4 bladder cancer (n ¼ 65) (Yeh et al, 2011). Overexpression of AXL was detected in 80% of samples, which exactly coincides with the proportion of Fra-1-positive T 2 -T 4 tumours revealed in this study.…”

Section: Discussionsupporting

confidence: 88%

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

et al. 2011

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Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscleinvasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

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“…19,43 However association and transactivation of AXL with EGFR and cMet would limit the effects of targeted therapies. 44,45 To comprehend the efficiency of SKI606 and MPCD84111 on the migration of TNBC cells we examined the targets of SKI606 and MPCD84111. Based on our experiments we concluded that SKI606 has 40% more cellular targets than MPCD84111 but still both compounds commonly affect the migration related Src family kinases ( Table 1 and Fig 4).…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells

Pénzes

Baumann

Szabadkai³

et al. 2014

Cancer Biology & Therapy

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Abbreviations: AKT, RAC-a serine/threonine-protein kinase; FAK, focal adhesion kinase; EGFR, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbant assay; Gas6, growth arrest specific 6; MAPK, mitogen activated protein kinases; PI3K, phosphatidylinositol 3-kinase; Pyk2, proline-rich tyrosine kinase 2; RTK, receptor tyrosine kinase; siRNA, short interfering RNA; TKI, tyrosine kinase inhibitor; TNBC, triple negative breast cancerBlocking the migration of metastatic cancer cells is a major goal in the therapy of cancer. The receptor tyrosine kinase AXL is one of the main triggers for cancer cell migration in neoplasia of breast, colon, skin, thyroid and prostate. In our study we analyzed the effect of AXL inhibition on cell motility and viability in triple negative breast cancer cell lines overexpressing AXL. Thereby we reveal that the compound BMS777607, exhibiting the lowest IC 50 values for inhibition of AXL kinase activity in the studied cell lines, attenuates cell motility to a lower extent than the kinase inhibitors MPCD84111 and SKI606. By analyzing the target kinases of MPCD84111 and SKI606 with kinase profiling assays we identified Lyn, a Src family kinase, as a target of both compounds. Knockdown of Lyn and the migrationrelated CRK-associated substrate (p130Cas), had a significant inhibitory effect on cell migration. Taken together, our findings highlight the importance of combinatorial or multikinase inhibition of non-receptor tyrosine kinases and AXL receptor tyrosine kinase in the therapy of triple negative breast cancer.

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Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

Cited by 67 publications

References 44 publications

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells

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