MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

Berggren, Kiersten L.; Cruz, Sebastian Restrepo; Hixon, M.D.; Cowan, Andrew T.; Keysar, Stephen B.; Craig, Stephanie G.; James, Jacqueline; Barry, Marc; Ozbun, Michelle A.; Jimeno, Antonio; McCance, Dennis J.; Beswick, Ellen J.; Gan, Gregory N.

doi:10.1038/s41388-019-0945-9

Cited by 14 publications

(13 citation statements)

References 52 publications

(77 reference statements)

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“…One possible explanation for our data diverging from previously published work is that many of these utilized different cancer types (i.e. intestinal tumors) or murine models (61)(62)(63)(64)(65). However, in patient derived data from TCGA, we note a significant association with improved 2-year survival in lung adenocarcinoma with high MK2 expression, Figure 5 Our data clearly show that a non-kinase function of MK2 is responsible for the observed sensitization to cell death, Figure 9.…”

Section: Discussioncontrasting

confidence: 74%

“…Overall, these mechanistic data provide biological rationale for the finding of reduced MK2 expression in late stage compared to early stage NSCLCs (Figure 4A). The logical extension of this mechanistic finding of reduced MK2 expression leading to resistance to cell death, resulting in more advanced stage NSCLC is intriguing but may not be transferable to other cancer types (61)(62)(63). For example, Henriques et al, demonstrate that intestinal carcinogenesis was related to MK2 kinase activity as chemical inhibition of MK2 led to decreased epithelial proliferation and reduced tumor growth (63).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the majority of data showing a role for MK2 in cancers focus on MK2 kinase activity and its role in tumor development (61)(62)(63)(64). In a novel murine model of NSCLC that generates MK2-proficient and MK2-deficient tumors within the same animal, Morandell et al show that MK2-proficient tumor area is consistently greater than MK2-deficient tumor area (65).…”

Section: Discussionmentioning

confidence: 99%

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MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival

Rosario

Suresh

Kallem

et al. 2021

Preprint

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Non-small cell lung cancers demonstrate intrinsic resistance to cell death even in response to chemotherapy. Previous work suggested that defective nuclear translocation of active caspase 3 may play a role in resistance to cell death. Separately, our group has identified that mitogen activated protein kinase activated protein kinase 2 (MK2) is required for nuclear translocation of active caspase 3 in the execution of apoptosis. This study demonstrates a relatively low expression of MK2 in non-small cell lung carcinoma cell lines compared to small cell carcinoma cell lines. Further, overexpression of MK2 in non-small cell lung carcinoma cell lines results in increased caspase 3 activity and caspase 3 mediated cell death. Higher MK2 transcript levels were observed in patients with earlier-stage non-small cell lung cancer. Higher expression of MK2 is associated with better survival in patients with early stage non-small cell lung cancer across two independent clinical datasets. Using data sets spanning multiple cancer types, we observed improved survival with higher MK2 expression was unique to lung adenocarcinoma. Mechanistically, MK2 promotes nuclear translocation of caspase 3 leading to PARP1 cleavage and execution of cell death. While MK2 can directly phosphorylate caspase 3, neither phosphorylation status of caspase 3 nor the kinase activity of MK2 impacts caspase 3 activation, nuclear translocation and execution of cell death. Rather, a non-kinase function of MK2, specifically trafficking via its nuclear localization sequence, is required for caspase 3 mediated cell death. In summary this study highlights the importance of a non-enzymatic function of MK2 in the execution of apoptosis, which may be leveraged in the adjunctive treatment of NSCLC or other conditions where regulation of apoptosis is crucial.

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival

Rosario

Suresh

Kallem

et al. 2021

Preprint

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“…Vitamin D down-regulated Heat shock protein beta-1 (HSP27), a multi-functional protein with well documented roles in HNC inflammation, proliferation, cancer progression, stemness, EMT, and more recently radio-sensitization and therapeutic resistance [21,[112][113][114][115][116][117]. Moreover, in SCC of the tongue HSP27 inhibition represses apoptosis and enhances sensitivity to chemotherapies [21] supporting a role for agents that reduce or impair HSP27.…”

Section: Discussionmentioning

confidence: 99%

Disparities in Head and Neck Cancer: A Case for Chemoprevention with Vitamin D

et al. 2020

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Blacks experience disproportionate head and neck cancer (HNC) recurrence and mortality compared to Whites. Overall, vitamin D status is inversely associated to HNC pointing to a potential protective linkage. Although hypovitaminosis D in Blacks is well documented it has not been investigated in Black HNC patients. Thus, we conducted a prospective pilot study accessing vitamin D status in newly diagnosed HNC patients stratified by race and conducted in vitro studies to investigate mechanisms associated with potential cancer inhibitory effects of vitamin D. Outcome measures included circulating levels of vitamin D, related nutrients, and risk factor characterization as well as dietary and supplemental estimates. Vitamin D-based in vitro assays utilized proteome and microRNA (miR) profiling. Nineteen patients were enrolled, mean circulating vitamin D levels were significantly reduced in Black compared to White HNC patients, 27.3 and 20.0 ng/mL, respectively. Whites also supplemented vitamin D more frequently than Blacks who had non-significantly higher vitamin D from dietary sources. Vitamin D treatment of HNC cell lines revealed five significantly altered miRs regulating genes targeting multiple pathways in cancer based on enrichment analysis (i.e., negative regulation of cell proliferation, angiogenesis, chemokine, MAPK, and WNT signaling). Vitamin D further altered proteins involved in cancer progression, metastasis and survival supporting a potential role for vitamin D in targeted cancer prevention.

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“…A posited etiologic mechanism for NIS involves inflammation secondary to cancer treatment and, in particular, treatment with targeted radiation [ 11 ]. While previous studies have provided that consuming a balanced and healthful diet rich in fruits and vegetables before treatment may abate inflammation and chronic NIS, research has yet to identify a generalizable dietary pattern that confers protection by mitigating inflammation after diagnosis and throughout cancer treatment [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Pretreatment Adherence to a Priori-Defined Dietary Patterns Is Associated with Decreased Nutrition Impact Symptom Burden in Head and Neck Cancer Survivors

et al. 2021

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Dietary intake is understood to contribute to nutrition impact symptoms (NIS) in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate the performance of four a priori-defined diet quality indices on the presence of NIS 1 year following diagnosis using data on 323 participants from the University of Michigan Head and Neck Specialized Program of Research Excellence (UM-SPORE). Pretreatment dietary intake was measured before treatment initiation using a food frequency questionnaire. NIS were measured along seven subdomains. Multivariable binary logistic regression models were constructed to evaluate relationships between pretreatment scores on a priori-defined diet quality indices (AHEI-2010, aMED, DASH, and a low-carbohydrate score) and the presence of individual symptoms in addition to a composite “symptom summary score” 1-year postdiagnosis. There were several significant associations between different indices and individual NIS. For the symptom summary score, there were significant inverse associations observed for aMED (ORQ5-Q1: 0.36, 95% CI: 0.14–0.88, ptrend = 0.04) and DASH (ORQ5-Q1: 0.38, 95% CI: 0.15–0.91, ptrend = 0.02) and the presence of NIS 1-year postdiagnosis. Higher adherence to the aMED and DASH diet quality indices before treatment may reduce NIS burden at 1-year postdiagnosis.

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MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

Cited by 14 publications

References 52 publications

MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival

MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival

Disparities in Head and Neck Cancer: A Case for Chemoprevention with Vitamin D

Pretreatment Adherence to a Priori-Defined Dietary Patterns Is Associated with Decreased Nutrition Impact Symptom Burden in Head and Neck Cancer Survivors

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