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Latent-Transforming Growth Factor β-Binding Protein 1/Transforming Growth Factor β1 Complex Drives Antitumoral

Alessandro Tubita¹, Alessio Menconi¹, Zoe Lombardi¹

¹Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy.

The American Journal of Pathology

|May 5, 2024

Abstract:

Melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. While available treatments have improved survival, long-term benefits are still unsatisfactory. The mitogen-activated protein kinase extracellular signal-regulated kinase 5 (ERK5) promotes melanoma growth, and ERK5 inhibition determines cellular senescence and the senescence-associated secretory phenotype. Here, latent-transforming growth factor β-binding protein 1 (LTBP1) mRNA was found to be up-regulated in A375 and SK-Mel-5 BRAF V600E melanoma cells after ERK5 inhibition. In keeping with a key role of LTBP1 in regulating transforming growth factor β (TGF-β), TGF-β1 protein levels were increased in lysates and conditioned media of ERK5-knockdown (KD) cells, and were reduced upon LTBP1 KD. Both LTBP1 and TGF-β1 proteins were increased in melanoma xenografts in mice treated with the ERK5 inhibitor XMD8-92. Moreover, treatment with conditioned media from ERK5-KD melanoma cells reduced cell proliferation and invasiveness, and TGF-β1-neutralizing antibodies impaired these effects. In silico data sets revealed that higher expression levels of both LTBP1 and TGF-β1 mRNA were associated with better overall survival of melanoma patients. Increased LTBP1 or TGF-β1 expression played a beneficial role in patients treated with anti-PD1 immunotherapy, making a possible immunosuppressive role of LTBP1/TGF-β1 unlikely upon ERK5 inhibition. This study, therefore, identifies additional desirable effects of ERK5 targeting, providing evidence of an ERK5-dependent tumor-suppressive role of TGF-β in melanoma.

Insights

Inhibiting extracellular signal-regulated kinase 5 (ERK5) in melanoma upregulates latent-transforming growth factor β-binding protein 1 (LTBP1) and transforming growth factor β (TGF-β1). This promotes tumor suppression and better patient survival, especially with anti-PD1 therapy.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Melanoma is an aggressive skin cancer with limited treatment options for advanced stages.
Extracellular signal-regulated kinase 5 (ERK5) drives melanoma progression.
ERK5 inhibition induces cellular senescence and alters the tumor microenvironment.

Purpose of the Study:

To investigate the role of ERK5 inhibition in melanoma.
To identify downstream targets of ERK5 in melanoma.
To explore the therapeutic potential of targeting ERK5 in melanoma.

Main Methods:

Utilized melanoma cell lines (A375, SK-Mel-5) with BRAF V600E mutation.
Performed ERK5 and LTBP1 knockdown (KD) experiments.
Administered ERK5 inhibitor (XMD8-92) to melanoma xenografts in mice.
Analyzed protein and mRNA levels of LTBP1 and TGF-β1.
Evaluated cell proliferation and invasiveness.
Correlated gene expression with patient survival data.

Main Results:

ERK5 inhibition upregulated latent-transforming growth factor β-binding protein 1 (LTBP1) mRNA in melanoma cells.
Transforming growth factor β (TGF-β1) protein levels increased upon ERK5 inhibition and decreased with LTBP1 knockdown.
LTBP1 and TGF-β1 proteins were elevated in vivo in xenografts treated with an ERK5 inhibitor.
Conditioned media from ERK5-inhibited cells reduced melanoma cell proliferation and invasiveness, an effect blunted by TGF-β1 neutralization.
Higher LTBP1 and TGF-β1 mRNA expression correlated with improved overall survival in melanoma patients.
These factors showed a beneficial role in patients receiving anti-PD1 immunotherapy.

Conclusions:

ERK5 inhibition promotes a tumor-suppressive TGF-β1 pathway in melanoma.
LTBP1 is a key mediator of ERK5 inhibition's effects on TGF-β1.
Targeting ERK5 offers potential therapeutic benefits by enhancing TGF-β1 signaling.
Elevated LTBP1 and TGF-β1 are favorable prognostic markers and may enhance immunotherapy efficacy.

Read full analysis

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