Effects of Raf kinase inhibitor protein expression on pancreatic cancer cell growth and motility: an in vivo and in vitro study

Dai, Hai-Su; Chen, Haowei; Liu, Wei; You, Yu; Tan, Jiaxin; Yang, Aigang; Lai, Xiangdong; Bie, Ping

doi:10.1007/s00432-016-2206-4

Cited by 16 publications

(10 citation statements)

References 39 publications

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“… 59 RKIP overexpression also enhanced metastatic ability in colorectal cancer 60 and increased tumor volume in pancreatic cancer. 61 From the evidence above, we can see a strong connection between RKIP expression and malignant tumor behaviors in vivo. We plan to explore the connection between NSCLC radioresistance and RKIP expression using tumor-bearing nude mice in our subsequent studies.…”

Section: Discussionmentioning

confidence: 90%

RKIP reduction enhances radioresistance by activating the Shh signaling pathway in non-small-cell lung cancer

Xie¹,

Li²,

Han³

et al. 2017

OTT

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Non-small-cell lung cancer (NSCLC) is exceptionally deadly because the tumors lack sensitive early-stage diagnostic biomarkers and are resistant to radiation and chemotherapy. Here, we investigated the role and mechanism of Raf kinase inhibitory protein (RKIP) in NSCLC radioresistance. The clinical data showed that the RKIP expression level was generally lower in radioresistant NSCLC tissues than in radiosensitive tissues. Reduced RKIP expression was related to NSCLC radioresistance and poor prognosis. In vitro experiments showed that RKIP knockdown increased radioresistance and metastatic ability in NSCLC cell lines. Mechanistically, RKIP reduction activated the Shh signaling pathway by derepressing Smoothened (Smo) and initiating glioma-associated oncogene-1 (Gli1)-mediated transcription in NSCLC. In addition, the inappropriately activated Shh–Gli1 signaling pathway then enhanced cancer stem cell (CSC) expression in the cell lines. The increasing quantity of CSCs in the tumor ultimately promotes the radiation resistance of NSCLC. Together, these results suggest that RKIP plays a vital role in radiation response and metastasis in NSCLC. RKIP reduction enhances radioresistance by activating the Shh signaling pathway and initiating functional CSCs. This role makes it a promising therapeutic target for improving the efficacy of NSCLC radiation treatment.

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Section: Discussionmentioning

confidence: 90%

RKIP reduction enhances radioresistance by activating the Shh signaling pathway in non-small-cell lung cancer

Xie¹,

Li²,

Han³

et al. 2017

OTT

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“…A protein interaction network analysis predicted that PEBP1 plays a critical role in mediating the interaction between RIPK4 and RAF1/MEK/ERK activation. PEBP1 is a physiological endogenous inhibitor of the RAF1/MEK/ERK pathway that can inhibit pancreatic cancer cell proliferation, migration and invasion ( 27 ); however, its association with RIPK4 remains unclear. PEBP1 can act as a signaling switch between the PKC and RAF1/MEK/ERK signaling cascades ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling

Zhang

et al. 2018

Int J Oncol

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Pancreatic cancer is a lethal disease with a high metastatic potential. In our previous study, we identified a specific subgroup of patients with pancreatic cancer with a serum signature of carcinoembryonic antigen (CEA)+/cancer antigen (CA)125+/CA19-9 ≥1,000 U/ml. In this study, by using high-throughput screening analysis, we found that receptor-interacting protein kinases 4 (RIPK4) may be a key molecule involved in the high metastatic potential of this subgroup of patients with pancreatic cancer. A high RIPK4 expression predicted a poor prognosis and promoted pancreatic cancer cell migration and invasion via the RAF1/MEK/ERK pathway. Moreover, RIPK4 activated the RAF1/MEK/ERK pathway by regulating proteasome-mediated phosphatidylethanolamine binding protein 1 (PEBP1) degradation. The suppression of PEBP1 degradation eliminated the RIPK4-induced activation of RAF1/MEK/ERK signaling and pancreatic cancer cell migration or invasion. Thus, on the whole, the findings of this study indicated that RIPK4 was upregulated in the subgroup of pancreatic cancer with a high metastatic potential. RIPK4 overexpression promoted pancreatic cancer cell migration and invasion via the PEBP1 degradation-induced activation of the RAF1/MEK/ERK pathway.

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“…MAPK signaling is known to be hyperactivated in cancer cells and associated with metastasis initiation and therapeutic resistance [14,84]. RKIP functions as a competitive blocker of MEK phosphorylation by interrupting the Raf-1/MEK association, through direct binding to the Raf-1 kinase domain which prevents Ser338 and Tyr340/341 phosphorylation by PAK and Src Kinases, needed for Raf-1 activation [3,14,85].…”

Section: Central Signaling Pathways Regulated By Rkipmentioning

confidence: 99%

RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact

Zaravinos

Bonavida

Chatzaki

et al. 2018

Cancers

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RAF-kinase inhibitor protein (RKIP) is a well-established tumor suppressor that is frequently downregulated in a plethora of solid and hematological malignancies. RKIP exerts antimetastatic and pro-apoptotic properties in cancer cells, via modulation of signaling pathways and gene products involved in tumor survival and spread. Here we review the contribution of RKIP in the regulation of early metastatic steps such as epithelial–mesenchymal transition (EMT), migration, and invasion, as well as in tumor sensitivity to conventional therapeutics and immuno-mediated cytotoxicity. We further provide updated justification for targeting RKIP as a strategy to overcome tumor chemo/immuno-resistance and suppress metastasis, through the use of agents able to modulate RKIP expression in cancer cells.

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Effects of Raf kinase inhibitor protein expression on pancreatic cancer cell growth and motility: an in vivo and in vitro study

Abstract: In conclusion, expression of RKIP is closely correlated with the survival of pancreatic cancer patients. RKIP can inhibit pancreatic adenocarcinoma cells proliferation, activities of migration and invasion, through downregulating Raf-1-MEK1/2-ERK1/2 signaling pathway.

Cited by 16 publications

References 39 publications

RKIP reduction enhances radioresistance by activating the Shh signaling pathway in non-small-cell lung cancer

RKIP reduction enhances radioresistance by activating the Shh signaling pathway in non-small-cell lung cancer

RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling

RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact

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