Hypoxia, immune cell infiltration, and drug delivery are key elements of therapeutic efficacy in solid tumors. Each are strongly influenced by the tumor microenvironment. Identification of novel methods to change the microenvironment is needed to improve the response of solid tumors, including melanoma, to therapies like immune checkpoint blockade. We and others have demonstrated that aerobic exercise remodels tumor microenvironment in multiple tumor types. Here, we present data to suggest that this exercise-induced remodeling of the tumor microenvironment is partially dependent on modulation of ERK5 in both tumor endothelium and infiltrating immune cells. The depletion of ERK5 in tumor-associated macrophages inhibits the growth of melanoma and lung carcinoma in mouse models, and the depletion of ERK5 in keratocytes prevents tumorigenesis promoted by inflammation. Multiple reports have shown the potential therapeutic approach of both ERK5 knockdown and pharmacological kinase inhibition in regulating inflammation and tumorigenesis. Here we identify the role of ERK5 S496 phosphorylation, known to promote inflammatory signaling, as a novel mediator of exercise induced tumor microenvironment alterations. Utilizing two melanoma models, we found that aerobic exercise suppresses the growth of YUMMER 1.7 tumors but not B16F10 in mice. Consistent with this, single cell RNA sequencing revealed reductions in myeloid derived suppressor cells and a shift in T cell populations favoring a non-exhausted phenotype in YUMMER 1.7. Flow cytometry evaluation demonstrated significantly more CD8+ T cells in YUMMER 1.7, but not in B16F10, tumors from exercised mice. Interestingly, we found increased phosphorylation of ERK5 at the S496 residue when ECs were treated with serum from exercised mice ex vivo. We also found the crucial role of ERK5 S496 phosphorylation in promoting both inflammation and proliferation in ERK5 TEY motif phosphorylation (kinase activity) and transactivation-independent manner in both ECs and macrophages. We generated ERK5 S496A knock-in mice, and found that the ability of exercise to suppress YUMMER 1.7 tumor growth was completely lost in ERK5 S496A knock-in mice, suggesting that ERK5 S496 phosphorylation is a key in exercise-induced tumor growth suppression. We are currently evaluating immune cell infiltration into tumors with or without exercise in the ERK5 S496A knock-in model relative to wild type mice. Our data suggest that ERK5 S496 phosphorylation is a critical mediator of the tumor microenvironment. The often neglected role of ERK5 S496 signaling should be carefully considered in the interpretation of prior reports of ERK5 knockdown and pharmacological kinase inhibition relative to tumorigenesis. Citation Format: Hannah Savage, Sumedha Pareek, Jonghae Lee, Riccardo Ballaro, Venkatasubrahman Samanthapudi, Kyung Ae Ko, Masaki Imanishi, Sivareddy Kotla, Jun-ichi Abe, Keri Schadler. Aerobic exercise suppresses melanoma tumor growth via upregulating ERK5 S496 phosphorylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 278.
Ceramides are essential sphingolipids that mediate cell death and survival. Low ceramide content in melanoma is one mechanism of drug resistance. Thus, increasing the ceramide content in tumor cells is likely to increase their sensitivity to cytotoxic therapy. Aerobic exercise has been shown to modulate ceramide metabolism in healthy tissue, but the relationship between exercise and ceramide in tumors has not been evaluated. Here, we demonstrate that aerobic exercise causes tumor cell apoptosis and accumulation of pro-apoptotic ceramides in B16F10 but not BP melanoma models using mice. B16F10 tumor-bearing mice were treated with two weeks of moderate treadmill exercise, or were control, unexercised mice. A reverse-phase protein array was used to identify canonical p53 apoptotic signaling as a key pathway upregulated by exercise, and we demonstrate increased apoptosis in tumors from exercised mice. Consistent with this finding, pro-apoptotic C16-ceramide, and the ceramide generating enzyme ceramide synthase 6 (CerS6), were higher in B16F10 tumors from exercised mice, while pro-survival sphingosine kinase 1 (Sphk1) was lower. These data suggest that exercise contributes to B16F10 tumor cell death, possibly by modulating ceramide metabolism toward a pro-apoptotic ceramide/sphingosine-1-phosphate balance. However, these results are not consistent in BP tumors, demonstrating that exercise can have different effects on tumors of different patient or mouse origin with the same diagnosis. This work indicates that exercise might be most effective as a therapeutic adjuvant with therapies that kill tumor cells in a ceramide-dependent manner.
Backgrounds A strong association between cardiovascular disease and Alzheimer’s disease (AD) has been reported, but its possible mechanism has been unknown. We have tested whether aortic endothelial function in AD is impaired and investigated the protective effect of exercise training (EX) on endothelial function in aorta of AD mice. METHODS Wild type (C57BL/6, WT) and AD (APP/PS1dE9, AD) mice underwent treadmill training (WT‐EX and AD‐EX) or remained sedentary for 12 weeks. The expression of total‐and phosphorylated‐endothelial nitric oxide synthase (t‐eNOS and p‐eNOS), beta‐amyloid, and superoxide dismutase 2 (SOD2) were quantified by Western blot analysis. RESULTS t‐eNOS and p‐eNOS expressions in AD were decreased compared to WT but EX increased both t‐eNOS and p‐eNOS in AD (P < 0.01 and P = 0.09). Beta‐amyloid levels in AD were higher compared to WT but EX decreased it (P < 0.05). SOD2 levels in AD were increased by EX (P < 0.05) whereas there was no change in WT. CONCLUSION Regular aerobic exercise alleviates e‐NOS‐mediated endothelial dysfunction in aorta of AD mice possibly via reduced beta‐amyloid and increased SOD2 levels.
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