Effects of RAL signal transduction in KRAS- and BRAF-mutated cells and prognostic potential of the RAL signature in colorectal cancer

Győrffy, Balázs; Stelniec-Klotz, Iwona; Sigler, Christian; Kasack, Katharina; Redmer, Torben; Yu, Qian; Schäfer, Reinhold

doi:10.18632/oncotarget.3871

Cited by 20 publications

(11 citation statements)

References 50 publications

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“…Current reports suggest that K-Ras may play a crucial role in regulating the progression of tumors, such as colon cancer (49) and cholangiocarcinoma (50). In addition, it can also activate multiple signaling pathways and regulate the procession of tumors (51)(52)(53). Meanwhile, the present clinical study found that not only the expression of K-Ras, PLCε, and PKCε was elevated in CRPC tissues, but K-Ras was also positively correlated with PLCε and PKCε, respectively.…”

Section: Discussionsupporting

confidence: 48%

RETRACTED: Inhibitor 9 Combined With Androgen Deprivation Therapy or Chemotherapy Delays the Malignant Behavior of Castration-Resistant Prostate Cancer Through K-Ras/PLCε/PKCε Signaling Pathway

et al. 2020

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Castration-resistant prostate cancer (CRPC) is a progressed stage of prostate cancer, which requires better understanding of the mechanisms and remains an unmet clinical need. As a common oncogene, K-Ras is associated with malignant behavior in different types of tumors but its role in CRPC is unknown. The present study aims to find the mechanism of K-Ras in CRPC and whether it can be used as a crucial molecule for the treatment of CRPC. For this purpose, tissue samples from primary prostate cancer (PPC) and CRPC patients were analyzed by immunohistochemistry and the data showed that K-Ras was elevated in CRPC. More importantly, higher K-Ras expression was related to a shorter recurrence-free survival time in patients with CRPC. In addition, K-Ras promoted the invasion, migration, and drug resistance of CRPC cells by activation of PLCε/PKCε signaling pathway. Meanwhile, the inhibitor of K-RasG12C mutants was able to inhibit malignant behavior of CRPC cells in vitro and in vivo. Inhibitors of K-RasG12C mutants have entered clinical trials. Taken together, the study shows that K-Ras may activate PKCε through PLCε, resulting in the alterations of malignant behavior of CRPC. Inhibitor 9, an inhibitor of the K-RasG12C mutant, has a strong anti-tumor effect in CRPC, which potentially suggests that inhibitors of this nature may serve as a promising treatment for CRPC.

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Section: Discussionsupporting

confidence: 48%

RETRACTED: Inhibitor 9 Combined With Androgen Deprivation Therapy or Chemotherapy Delays the Malignant Behavior of Castration-Resistant Prostate Cancer Through K-Ras/PLCε/PKCε Signaling Pathway

et al. 2020

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“…The p-value was determined by one-tailed Welch’s t-test, denoted in the figures as: *** for p<0.001, ** for p<0.01, and * for p<0.05. C. Kaplan–Meier survival plots in colon cancer patients with high and low levels of Ate1 mRNA of were generated utilizing a previously established database ( 21 ). The following datasets were used: GSE12945 GSE14333 GSE17538 GSE31595 GSE33114 GSE37892 GSE38832 GSE39582 and GSE41258.…”

Section: Figurementioning

confidence: 99%

Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers

et al. 2015

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Arginylation is an emerging posttranslational modification mediated by arginyltransferase (ATE1) that is essential for mammalian embryogenesis and regulation of the cytoskeleton. Here, we discovered that Ate1 knockout embryonic fibroblasts exhibit tumorigenic properties, including abnormally rapid contact-independent growth, reduced ability to form cell-cell contacts, and chromosomal aberrations. Ate1 knockout fibroblasts can form large colonies in Matrigel and exhibit invasive behavior, unlike wild type fibroblasts. Furthermore, Ate1 knockout cells form tumors in subcutaneous xenograft assays in immunocompromised mice. Abnormal growth in these cells can be partially rescued by reintroduction of stably expressed specific Ate1 isoforms, which also reduce the ability of these cells to form tumors. Tumor array studies and bioinformatics analysis show that Ate1 is down-regulated in several types of human cancer samples at the protein level, and that its transcription level inversely correlates with metastatic progression and patient survival. We conclude that Ate1 knockout results in carcinogenic transformation of cultured fibroblasts, suggesting that in addition to its previously known activities Ate1 gene is essential for tumor suppression and also likely participates in suppression of metastatic growth.

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“…Ras-like (Ral) GTPases include RalA and RalB, which both have differential functions (24). In several types of cancers, increased expression of RalA has been identified (25)(26)(27). Consistent with these studies, according to the GEO dataset (Access ID: GSE45016), we found increased expression levels of RalA in prostate cancer tissues.…”

Section: Discussionmentioning

confidence: 99%

Subcellular localization of aquaporin 3 in prostate cancer is regulated by RalA

et al. 2018

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We previously found that in normal epithelia of the prostate, localization of AQP3 is limited to the cell membranes; however, the expression of AQP3 protein in cancer epithelia is distributed to the plasma. Yet, the detailed mechanism remains unclear. In the present study, PC‑3 cell derivatives with stable knockdown of RAS like proto‑oncogene A (RalA) and overexpression of E‑cadherin were established. We found that overexpression of E‑cadherin and knockdown of RaLA resulted in an increase in AQP3 in prostate cancer cell plasma membranes. In order to investigate the functions caused by of the AQP3 redistribution in prostate cancer cells, the growth function of AQP3 redistribution was detected with clonogenic, MTT and MTS assays. In regards to the effect on apoptosis, flow cytometric analysis and DNA Ladder TUNEL assay were utilized. The results showed that AQP3 redistribution in PC‑3 cells significantly inhibited the proliferation of cells and enhanced cell apoptosis compared with these parameters in the control. Wound healing assay and Matrigel assays determined that knockout of RalA inhibited the motility and invasion capability of PC‑3 cells. To investigate the molecular mechanism involved in AQP3 redistribution in PC‑3 cells, the level of cAMP in PC‑3 cells was examined, and the results showed that AQP3 distribution was regulated through cAMP/PKA/RalA signal pathways. In conclusion, these studies suggest a novel function of AQP3, and provide a creative view for RalA-directed therapies.

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Effects of RAL signal transduction in KRAS- and BRAF-mutated cells and prognostic potential of the RAL signature in colorectal cancer

Cited by 20 publications

References 50 publications

RETRACTED: Inhibitor 9 Combined With Androgen Deprivation Therapy or Chemotherapy Delays the Malignant Behavior of Castration-Resistant Prostate Cancer Through K-Ras/PLCε/PKCε Signaling Pathway

RETRACTED: Inhibitor 9 Combined With Androgen Deprivation Therapy or Chemotherapy Delays the Malignant Behavior of Castration-Resistant Prostate Cancer Through K-Ras/PLCε/PKCε Signaling Pathway

Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers

Subcellular localization of aquaporin 3 in prostate cancer is regulated by RalA

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