Divergent Roles for RalA and RalB in Malignant Growth of Human Pancreatic Carcinoma Cells

Lim, Kian-Huat; O’Hayer, Kevin; Adam, Stacey J.; Kendall, S. DiSean; Campbell, Paul M.; Der, Channing J.; Counter, Christopher M.

doi:10.1016/j.cub.2006.10.023

Cited by 218 publications

(258 citation statements)

References 36 publications

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“…RALA is important for tumor growth, whereas RALB is important for tumor metastasis and inva sion [21,25,[52][53][54] . However, it has also been reported a number of times that www.nature.com/aps Guin S et al Acta Pharmacologica Sinica npg both isoforms also have redundant functions in cancer [24,54,55] .…”

Section: Ral In Cancermentioning

confidence: 99%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. Review RAS GTPase overviewRAS is the most extensively studied GTPase [1] . It is known to regulate various cellular functions, including proliferation, survival, growth, migration, differentiation and cytoskeletal dynamics [2][3][4] (Figure 1). Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] . These encode the related proteins HRAS, KRAS and NRAS, respectively, of 189 amino acids in length [1,4] . KRAS exists as two isoforms, 4A and 4B, which are generated by alternative exon splicing [10] . These different RAS genes are well known to have differential cellular specificities and intrinsic transforming potentials [3,4,10] .In normal cells, RAS proteins act as molecular switches for critical cellular functions. RAS proteins are activated by upstream receptors such as receptor tyrosine kinases * To whom correspondence should be addressed. E-mail dan.theodorescu@ucdenver.edu Received 2014-08-07 Accepted 2014-10-30 Figure 1. RAS GTPase activation and downstream signaling. The cartoon shows the mechanism of RAS GTPase activation by upstream stimuli and numerous downstream effectors stimulated by activated RAS. RAS regulates critical cellular functions through these effectors. Constitutive RAS activation due to mutations leads to protumorigenic signaling through these effectors.

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Section: Ral In Cancermentioning

confidence: 99%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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“…Studies demonstrated the importance of RalA and, more specifically, phosphorylation at S194 by AAK, in tumor development (6, 7, 10). The importance of RalA S194 phosphorylation in tumorigenesis makes AAK an attractive druggable target downstream of oncogenic Ras activation.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence for the importance of the RalA and RalB small GTPases in mutant Ras-driven oncogenesis (4, 5). RNAi knockdown of endogenous RalA in PDAC cells significantly impaired anchorage-independent growth whereas knockdown of RalB impaired Matrigel invasion in vitro and experimental metastasis in vivo (6). Importantly, RalA-GTP and RalB-GTP levels were significantly higher in PDAC cell lines and in patient tumors relative to normal matched and unmatched samples (6, 7).…”

Section: Introductionmentioning

confidence: 99%

“…RNAi knockdown of endogenous RalA in PDAC cells significantly impaired anchorage-independent growth whereas knockdown of RalB impaired Matrigel invasion in vitro and experimental metastasis in vivo (6). Importantly, RalA-GTP and RalB-GTP levels were significantly higher in PDAC cell lines and in patient tumors relative to normal matched and unmatched samples (6, 7). Taken together, these studies suggest that therapeutic inhibition of Ral may be an effective therapy for KRAS mutant PDAC.…”

Section: Introductionmentioning

confidence: 99%

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Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

Neel

Stratford

Shinde

et al. 2014

Molecular Cancer Therapeutics

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The high prevalence of KRAS mutations and importance of the RalGEF-Ral pathway downstream of activated K-Ras in pancreatic ductal adenocarcinoma (PDAC) emphasize the importance of identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase is critical for PDAC tumorigenesis. We sought to evaluate the Aurora A kinase-selective inhibitor MLN8237 as a potential indirect anti-RalA targeted therapy for PDAC. We utilized a site-specific phospho-S194 RalA antibody and determined that RalA S194 phosphorylation levels were elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate that MLN8237 treatment may be effective for a subset of PDAC patients independent of RalA S194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment.

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“…Overrepresentation of Ral-regulated genes in a set of genes differentially expressed in human bladder cancer strongly suggests that transcriptional regulation by RalA and RalB contributes significantly to the development of human bladder cancer. However, because higher RalA and RalB activation states are thought to contribute to cancer formation and progression (Lim et al, 2005(Lim et al, , 2006, the siRNA-mediated approach we took may have uncovered different Ralregulated genes than those regulated by endogenously activated Ral in cancer cells. With Ral depletion triggering both increases and decreases in gene expression, dissecting out the complex relationships between RalA/B activation status and specific gene expression changes in bladder cancer progression will require further experiments.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

2007

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Although the monomeric GTPases RalA and RalB have been shown to regulate a variety of transcription factors, little is known regarding the differences or similarities in transcriptional programs regulated by RalA compared to RalB. Further, the association of these transcriptional pathways to human carcinogenesis and progression remains unclear. Here, we studied the role of RalA and/ or RalB in transcriptional regulation by combining short interfering RNA depletion of Ral with gene expression profiling via microarray in the human bladder cancer cell line, UMUC-3. A large number of genes were found to be similarly modulated in cells with RalA and RalB depletion, suggesting that RalA and RalB impinge on overlapping transcriptional signaling pathways. However, smaller sets of genes were modulated by depletion of RalA or RalB, indicating that these closely related proteins also regulate nonoverlapping transcriptional pathways. Computational analysis of upstream sequences of genes modulated by Ral depletion identified Ras-responsive element-binding protein (RREB)-1, as a putative Ral transcriptional target, which we verified experimentally. Importantly, as a group, Ral-regulated probe sets identified here were disproportionally represented among those differentially expressed as a function of human bladder transformation. Taken together, these data strongly suggest that Ral family members mediate both common and specific transcriptional programs that are associated with human cancer and identify RREB-1 as a novel transcriptional effector of Ral.

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Divergent Roles for RalA and RalB in Malignant Growth of Human Pancreatic Carcinoma Cells

Abstract: RalA function is critical to tumor initiation, whereas RalB function is more important for tumor metastasis in the tested cell lines and thus argues for critical, but distinct, roles of Ral proteins during the dynamic progression of Ras-driven pancreatic cancers.

Cited by 218 publications

References 36 publications

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

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