Myc inhibition tips the immune balance to promote antitumor immunity

Yang, Chao; Liu, Yun; Hu, Yudi; Fang, Liang; Huang, Zhanwen; Cui, Huanhuan; Xie, Jun; Hong, Yazhen; Chen, Wei; Xiao, Nengming; Li, Qiyuan; Liu, Wen-Hsien; Xiao, Changchun

doi:10.1038/s41423-022-00898-7

Cited by 12 publications

(7 citation statements)

References 37 publications

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“…MYC can reshape the tumor microenvironment, evading host immune responses ( 98 ). Myc inhibitors decrease the stable state of regulatory T (Treg) cells in tumors and the differentiation of resting treg (rTreg) to activated Treg (aTreg), which activates CD8 + T cells and induces anti-tumor immune response ( 99 ). Cysteine Aspartic protease 3 (CASP3) serves as the primary mediator of apoptosis in tumor cells when exposed to cytotoxic drugs, radiotherapy, or immunotherapy, making it a commonly employed marker for assessing the efficacy of cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Bazhen decoction in the treatment of colorectal cancer based on network pharmacology, molecular docking, and experimental validation

Lu,

Sun,

Zhou

et al. 2023

Front. Immunol.

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ObjectiveBazhen Decoction (BZD) is a common adjuvant therapy drug for colorectal cancer (CRC), although its anti-tumor mechanism is unknown. This study aims to explore the core components, key targets, and potential mechanisms of BZD treatment for CRC.MethodsThe Traditional Chinese Medicine Systems Pharmacology (TCMSP) was employed to acquire the BZD’s active ingredient and targets. Meanwhile, the Drugbank, Therapeutic Target Database (TTD), DisGeNET, and GeneCards databases were used to retrieve pertinent targets for CRC. The Venn plot was used to obtain intersection targets. Cytoscape software was used to construct an “herb-ingredient-target” network and identify core targets. GO and KEGG pathway enrichment analyses were conducted using R language software. Molecular docking of key ingredients and core targets of drugs was accomplished using PyMol and Autodock Vina software. Cell and animal research confirmed Bazhen Decoction efficacy and mechanism in treating colorectal cancer.ResultsBZD comprises 173 effective active ingredients. Using four databases, 761 targets related to CRC were identified. The intersection of BZD and CRC yielded 98 targets, which were utilized to construct the “herb-ingredient-target” network. The four key effector components with the most targets were quercetin, kaempferol, licochalcone A, and naringenin. Protein-protein interaction (PPI) analysis revealed that the core targets of BZD in treating CRC were AKT1, MYC, CASP3, ESR1, EGFR, HIF-1A, VEGFR, JUN, INS, and STAT3. The findings from molecular docking suggest that the core ingredient exhibits favorable binding potential with the core target. Furthermore, the GO and KEGG enrichment analysis demonstrates that BZD can modulate multiple signaling pathways related to CRC, like the T cell receptor, PI3K-Akt, apoptosis, P53, and VEGF signaling pathway. In vitro, studies have shown that BZD dose-dependently inhibits colon cancer cell growth and invasion and promotes apoptosis. Animal experiments have shown that BZD treatment can reverse abnormal expression of PI3K, AKT, MYC, EGFR, HIF-1A, VEGFR, JUN, STAT3, CASP3, and TP53 genes. BZD also increases the ratio of CD4+ T cells to CD8+ T cells in the spleen and tumor tissues, boosting IFN-γ expression, essential for anti-tumor immunity. Furthermore, BZD has the potential to downregulate the PD-1 expression on T cell surfaces, indicating its ability to effectively restore T cell function by inhibiting immune checkpoints. The results of HE staining suggest that BZD exhibits favorable safety profiles.ConclusionBZD treats CRC through multiple components, targets, and metabolic pathways. BZD can reverse the abnormal expression of genes such as PI3K, AKT, MYC, EGFR, HIF-1A, VEGFR, JUN, STAT3, CASP3, and TP53, and suppresses the progression of colorectal cancer by regulating signaling pathways such as PI3K-AKT, P53, and VEGF. Furthermore, BZD can increase the number of T cells and promote T cell activation in tumor-bearing mice, enhancing the immune function against colorectal cancer. Among them, quercetin, kaempferol, licochalcone A, naringenin, and formaronetin are more highly predictive components related to the T cell activation in colorectal cancer mice. This study is of great significance for the development of novel anti-cancer drugs. It highlights the importance of network pharmacology-based approaches in studying complex traditional Chinese medicine formulations.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Bazhen decoction in the treatment of colorectal cancer based on network pharmacology, molecular docking, and experimental validation

Lu,

Sun,

Zhou

et al. 2023

Front. Immunol.

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“…Numerous studies have consistently demonstrated that targeting MYC activity or expression results in a notable reduction in tumor growth across diverse preclinical tumor models [ 20 , 21 , 46 , 187 , 188 ]. Notably, emerging evidence highlights the impact of MYC deregulation in suppressing the immune response to tumors, whereas inhibiting MYC activity shows promise in stimulating an anti-tumor response [ 55 , 99 , 100 , 133 , 134 , 135 ]. Future research should focus on establishing the broader potential of MYC inhibitors in enhancing anti-tumor immunity.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“…MYC inhibition reverses the immunosuppressive tumor microenvironment, restores immune cell activation and enhances the production of immune-stimulatory molecules [ 133 , 134 , 135 , 136 ]. Preclinical studies demonstrate the potential of MYC inhibition to improve immune response and synergize with immunotherapies [ 137 , 138 , 139 ].…”

Section: Myc As a Regulator Of The Tumor Microenvironment Leading To ...mentioning

confidence: 99%

Unraveling MYC’s Role in Orchestrating Tumor Intrinsic and Tumor Microenvironment Interactions Driving Tumorigenesis and Drug Resistance

Doha,

Sears

2023

Pathophysiology

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The transcription factor MYC plays a pivotal role in regulating various cellular processes and has been implicated in tumorigenesis across multiple cancer types. MYC has emerged as a master regulator governing tumor intrinsic and tumor microenvironment interactions, supporting tumor progression and driving drug resistance. This review paper aims to provide an overview and discussion of the intricate mechanisms through which MYC influences tumorigenesis and therapeutic resistance in cancer. We delve into the signaling pathways and molecular networks orchestrated by MYC in the context of tumor intrinsic characteristics, such as proliferation, replication stress and DNA repair. Furthermore, we explore the impact of MYC on the tumor microenvironment, including immune evasion, angiogenesis and cancer-associated fibroblast remodeling. Understanding MYC’s multifaceted role in driving drug resistance and tumor progression is crucial for developing targeted therapies and combination treatments that may effectively combat this devastating disease. Through an analysis of the current literature, this review’s goal is to shed light on the complexities of MYC-driven oncogenesis and its potential as a promising therapeutic target.

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“…One study showed that pharmacological inhibition of MYC by 10058-F4 resulted in changes in lipid and amino acid metabolism in neuroblastoma cell lines ( 160 ). Additionally, another MYC-MAX perturbagen, Mycro3 resulted in enhanced CD8 + T cell function in surveilling cancer cells and inducing anti-tumor immune response ( 161 ). Another approach is the inhibition of MYC transcription by bromodomain-containing 4 (BRD4), using inhibitors such as JQ1 and OTX-015 ( 162 ).…”

Section: Targeting Myc To Tackle Oncometabolism and Oncoimmunology: 2...mentioning

confidence: 99%

Targeting MYC at the intersection between cancer metabolism and oncoimmunology

Venkatraman,

Balasubramanian,

Thuwajit

et al. 2024

Front. Immunol.

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MYC activation is a known hallmark of cancer as it governs the gene targets involved in various facets of cancer progression. Of interest, MYC governs oncometabolism through the interactions with its partners and cofactors, as well as cancer immunity via its gene targets. Recent investigations have taken interest in characterizing these interactions through multi-Omic approaches, to better understand the vastness of the MYC network. Of the several gene targets of MYC involved in either oncometabolism or oncoimmunology, few of them overlap in function. Prominent interactions have been observed with MYC and HIF-1α, in promoting glucose and glutamine metabolism and activation of antigen presentation on regulatory T cells, and its subsequent metabolic reprogramming. This review explores existing knowledge of the role of MYC in oncometabolism and oncoimmunology. It also unravels how MYC governs transcription and influences cellular metabolism to facilitate the induction of pro- or anti-tumoral immunity. Moreover, considering the significant roles MYC holds in cancer development, the present study discusses effective direct or indirect therapeutic strategies to combat MYC-driven cancer progression.

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Myc inhibition tips the immune balance to promote antitumor immunity

Cited by 12 publications

References 37 publications

Mechanism of Bazhen decoction in the treatment of colorectal cancer based on network pharmacology, molecular docking, and experimental validation

Mechanism of Bazhen decoction in the treatment of colorectal cancer based on network pharmacology, molecular docking, and experimental validation

Unraveling MYC’s Role in Orchestrating Tumor Intrinsic and Tumor Microenvironment Interactions Driving Tumorigenesis and Drug Resistance

Targeting MYC at the intersection between cancer metabolism and oncoimmunology

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