Overexpression of MSK1 is associated with tumor aggressiveness and poor prognosis in colorectal cancer

Fu, Xiaohong; Fan, Xinjuan; Hu, Jun; Zou, Hongzhi; Chen, Zhiting; Liu, Qi; Ni, Beibei; Tan, Xiaoli; Qiao, Shan; Wang, Jingxuan; Wang, Lei; Wang, Jianping

doi:10.1016/j.dld.2017.02.009

Cited by 13 publications

(18 citation statements)

References 27 publications

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“…Engagement of parallel pathways, such as JNK/JUN axis, which has been previously shown to play a role in evolution of melanoma resistance to BRAF inhibition (8,9), may shield downstream effectors connected to MAPK pathway from upstream inhibition, even at the convergence point of ERK. Although a recent study indicates that MSK1 expression correlates with colorectal cancer aggressiveness and poor prognosis, the role of MSK1 as well as other parallel inputs in MAPK inhibitor resistance in this disease has not been extensively explored to date (35). Thus, combination treatments that include inhibitors within MAPK pathway as well as parallel signaling axes may be necessary to fully address the complexity of resistance in KRAS-mutant malignancies, such as those represented by the CXF-243 KRAS-mutant colorectal cancer PDX herein.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance

Aronchik¹,

Dai²,

Labenski³

et al. 2019

Molecular Cancer Research

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As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the MAPK pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant BRAF-activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003, was characterized and shown to be active in preclinical models of KRAS-mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS-mutant patient-derived xenograft (PDX) model of colorectal cancer. Finally, combination of CC-90003 with docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming. Implications: Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS-mutant tumors, which present a therapeutic challenge for currently available therapies.

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Section: Discussionmentioning

confidence: 99%

Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance

Aronchik¹,

Dai²,

Labenski³

et al. 2019

Molecular Cancer Research

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“…Previous studies have shown that MSK1 is essential for proliferation of breast cancer cells [15] and malignant phenotype of Ciras-3 cells [17]. Overexpression of MSK1 aggravated tumor aggression and poor prognosis in colorectal cancer [18]. MSK1 was also implicated in gastric cancer [19] and skin tumor development [20].…”

Section: Discussionmentioning

confidence: 99%

“…MSK1 knockdown inhibited anchorage-independent growth of Ciras-3 cells and improved their malignant phenotype [17]. Overexpression of MSK1 triggered tumor invasion and poor prognosis in colorectal cancer [18]. Furthermore, MSK1 was implicated in gastric cancer [19] and skin tumor development [20].…”

Section: Introductionmentioning

confidence: 99%

MSK1 promotes cell proliferation and metastasis in uveal melanoma by phosphorylating CREB

Liu¹,

Liu²,

Wang³

et al. 2020

aoms

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Introduction: Uveal melanoma is known as a frequent intraocular tumor, with high metastasis and poor prognosis. Mitogen-and stress-activated protein kinase 1 (MSK1) is a serine/threonine kinase that has been reported to be associated with tumor progression in several types of human cancer. However, the role of MSK1 has rarely been studied in uveal melanoma and the underlying mechanism remained unclear. Material and methods: The expression level of MSK1 in human uveal melanoma tissues and normal uveal tissues was determined by qRT-PCR analysis, western blotting and immunohistochemistry (IHC). Subsequently, MTT assay, colony formation assay and flow cytometry assay were performed to assess the effects of MSK1 on cell proliferation. Wound-healing and transwell chamber assays were adopted to clarify the role of MSK1 in cell metastasis. Finally, the function of MSK1 was confirmed in vivo in a tumor-bearing mouse model. Results: The expression levels of MSK1 and p-cyclic AMP-responsive element binding protein (CREB) were strongly up-regulated in human uveal melanoma tissues. MSK1 overexpression facilitated cell viability and clone formation, and promoted migration and invasion of uveal melanoma cells. However, mutation of cyclic AMP-responsive element binding protein (CREB) at Ser133 residues reversed the effect of MSK1 on uveal melanoma cell proliferation and metastasis. The in vivo experiment suggested that the tumor weight was lower and the tumor mass grew more slowly in the shMSK1 group as compared to the shNC group. Conclusions: MSK1 promotes proliferation and metastasis of uveal melanoma cells by phosphorylated CREB at Ser133 residues. Therefore, MSK1 could be a promising candidate for uveal melanoma therapy and especially has tremendous potential in the treatment of cancers in which the MSK1-CREB pathway is abnormally active.

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“…For example, treatment of colon cancer line HCT116 with the drug Oridonin has to been shown to induce antiproliferative and pro-apoptotic effects on the cancer cells through phosphorylation of P38 [5]. Other studies, however suggest the p38 MAPK pathway may play a fundamental role in the pathogenesis of colon cancer as well as other types of cancers such as those of the lung, liver, breast, prostate, and bladder [6,7,8,9,10,11,12,13]. In addition, inhibition of p38 MAPK has been shown to increase the sensitivity of human colon cancer cells to 5-fluorouracil treatment [14].…”

Section: Introductionmentioning

confidence: 99%

Activation of the P38-MSK1 axis in colorectal adenocarcinoma determines a good prognostic outcome

Gayyed¹,

Soliman²,

Ahmed³

et al. 2021

pjp

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Colorectal cancer (CRC) is the third most common cancer worldwide and is associated with a high level of mortality and morbidity. In this study we evaluate expression of p-p38 and p-MSK1 in CRC and determine whether there is an association between expression of these markers and any clinicopathologic parameters that could be of prognostic value. Expression of p-p38, p-MSK1 and ki-67 were examined by immunohistochemistry in 135 archival CRC cases and the findings were correlated with the patient clinicopathological data. P-p38 and p-MSK1 were expressed at high level in 58.5 % and 60.7% of CRC cases respectively. A statistically significant negative correlation was found between expression of p-p38 and Ki-67 (p < 0.001, r = -0.63) and between p-MSK1 and Ki-67 expression (p < 0.001, r = -0.61). The majority of CRC cases expressing high levels of p-p38 also expressed high levels of p-MSK1 and this correlation was highly significant (p < 0.001, r = 0.863). The high expression of p-p38 and p-MSK1 was also significantly associated with low Dukes and TNM stage. The elevated expression of p-38 and p-MSK1 in CRC was associated with a good prognosis and prolonged overall survival (p < 0.001, each). Our finding showed that activation of the p38-MSK1 axis determines a good outcome in CRC.

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Overexpression of MSK1 is associated with tumor aggressiveness and poor prognosis in colorectal cancer

Cited by 13 publications

References 27 publications

Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance

Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance

MSK1 promotes cell proliferation and metastasis in uveal melanoma by phosphorylating CREB

Activation of the P38-MSK1 axis in colorectal adenocarcinoma determines a good prognostic outcome

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