RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF‐κB pathway in oral squamous cell carcinoma

Abstract

Receptor for activated C kinase 1 (RACK1) has been shown to promote oral squamous cell carcinoma (OSCC) progression, and RACK1 expression levels have been negatively correlated with prognosis in patients with OSCC. Here, we investigated the impact of RACK1 OSCC expression on the recruitment and differentiation of tumor‐associated macrophages. High RACK1 expression in OSCC cells correlated with increased M2 macrophage infiltration in tumor samples from a clinical cohort study. Moreover, the combination of RACK1 expression and the M2/M1 ratio could successfully predict prognosis in OSCC. OSCC cells with high RACK1 expression inhibited the migration of THP‐1 cells, promoted M2‐like macrophage polarization in vitro, and increased the proportion of M2‐like macrophages in a xenograft mouse model. Moreover, both M1‐ and M2‐like macrophage polarization‐associated proteins were induced in macrophages cocultured with RACK1‐silenced cell supernatant. A mechanistic study revealed that the expression and secretion of C‐C motif chemokine 2 (CCL2), C‐C motif chemokine 5 (CCL5), interleukin‐6 (IL‐6), and interleukin‐1 (IL‐1) are closely related to RACK1 expression. In addition, blocking nuclear factor‐kappa B (NF‐κB) could promote M2‐like macrophage polarization. These results indicate that RACK1 and the M2/M1 ratio are predictors of a poor prognosis in OSCC. RACK1 promotes M2‐like polarization by regulating NF‐κB and could be used as a potential therapeutic target for antitumor immunity.

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

“…There are controversial data about the function of macrophages in cancer cells (Mantovani, Sozzani, Locati, Allavena, & Sica, 2002). The tumor‐associated macrophages (TAMs) reveal M2 phenotype that are associated with invasion and migration of cancer cells, while M1 macrophages have anti‐inflammatory and onco‐suppressor characteristics (Dan et al, 2020; Zhou, Yang, & Li, 2019). It is worth mentioning that macrophages alter their phenotype in response to environmental stimuli.…”

The Role of Macrophages in Oral Squamous Cell Carcinoma

“…Co-culture of a monocyte/macrophage like cell line (RAW264.7) with conditioned medium derived from OSCC cell lines stimulated the expression of pro-tumor cytokines and chemokines associated with the M2 phenotype, e.g., IL-10, CCL22, and VEGF-A ( 54 ). The receptor for activated C kinase 1 (RACK1) has also been shown to induce OSCC progression, by favoring the polarization toward the M2 phenotype and reducing the levels of M1-phenotype related molecules, such as IL-6, CCL5, and CSF, in an NF-kB axis-dependent manner ( 55 ). TAMs-induced VEGF expression in OSCC has also been associated with activation of the TGF-β1/TβRII/Smad3 signaling pathway ( 56 ).…”

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

“…RACK1 stabilises PP2A [ 140 ], and PP2A-associated immune suppression [ 123 ]. RACK1 also induces immune suppression by increasing the M2/M1 macrophage ratio [ 141 ] and suppressing the numbers of CD4+, CD8+, and iNK T cells [ 142 ], as well as promoting the EMT [ 143 ]. As RACK1, in interaction with GSK3α, can regulate the circadian clock in mammalian cells [ 144 ], alterations in RACK1 levels and its interactions are likely to have wider circadian-driven immune-regulatory consequences.…”