Creatine promotes cancer metastasis through activation of Smad2/3

Zhang, Liwen; Zhu, Zijing; Yan, Huiwen; Wang, Wen; Wu, Zhenzhen; Zhang, Fei; Zhang, Qixiang; Shi, Guizhi; Du, Jun; Cai, Hongfei; Zhang, Xuanxuan; Hsu, David S.; Gao, Pu; Piao, Hulin; Chen, Gang; Bu, Pengcheng

doi:10.1016/j.cmet.2021.03.009

Cited by 83 publications

(55 citation statements)

References 48 publications

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“…Interesting results were obtained from Enrichr using the miRTarBase data library to analyze the miRNAs interactions. Regarding cancer, recent evidence has suggested that Cr supplementation might have a carcinogenic effect [ 117 ]; nevertheless, contrary to this hypothesis, the formation of carcinogenic heterocyclic amines is unrelated to CrM supplementation [ 118 ], and even clinical research has demonstrated a potential anti-tumor progression [ 119 ]. In fact, downregulation of the CK isozymes and low levels of PCr and Cr are associated with sarcoma and adenocarcinoma progression [ 120 ].…”

Section: Discussionmentioning

confidence: 99%

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

et al. 2021

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Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis with sites of ATP consumption (the CK/PCr system). Supplementation with creatine monohydrate (CrM) can enhance this system, resulting in well-known ergogenic effects and potential health or therapeutic benefits. In spite of our vast knowledge about these molecules, no integrative analysis of molecular mechanisms under a systems biology approach has been performed to date; thus, we aimed to perform for the first time a convergent functional genomics analysis to identify biological regulators mediating the effects of Cr supplementation in health and disease. A total of 35 differentially expressed genes were analyzed. We identified top-ranked pathways and biological processes mediating the effects of Cr supplementation. The impact of CrM on miRNAs merits more research. We also cautiously suggest two dose–response functional pathways (kinase- and ubiquitin-driven) for the regulation of the Cr uptake. Our functional enrichment analysis, the knowledge-based pathway reconstruction, and the identification of hub nodes provide meaningful information for future studies. This work contributes to a better understanding of the well-reported benefits of Cr in sports and its potential in health and disease conditions, although further clinical research is needed to validate the proposed mechanisms.

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Section: Discussionmentioning

confidence: 99%

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

et al. 2021

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“…Whether cCr monotherapy blocks primary tumor growth was not tested. Of interest, recent studies in a liver cancer model (HCT116) and in the 4T1 model [95], creatine supplementation, which increases creatine kinase flux, was not sufficient to change primary tumor growth rate, but significantly promoted lung metastasis in mice bearing 4T1 cells.…”

Section: Discussionmentioning

confidence: 99%

HIF-dependent CKB expression promotes breast cancer metastasis, whereas cyclocreatine therapy impairs cellular invasion and improves chemotherapy efficacy

Krutilina

Playa

Schwab

et al. 2021

Preprint

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The oxygen-responsive Hypoxia Inducible Factor (HIF)–1 promotes several steps of the metastatic cascade. A hypoxic gene signature is enriched in triple negative breast cancers (TNBCs), which correlates with poor patient survival. Since inhibiting the HIF transcription factors with small molecules is challenging, we sought to identify genes downstream of HIF-1 that could be targeted to block invasion and metastasis. Creatine kinase brain isoform (CKB) was identified as a highly differentially expressed gene in a screen of HIF-1 wild type and knockout mammary tumor cells derived from a transgenic model of metastatic breast cancer. CKB is a cytosolic enzyme that reversibly catalyzes the phosphorylation of creatine, generating phosphocreatine (PCr) in the forward reaction, and regenerating ATP in the reverse reaction. Creatine kinase activity is inhibited by the creatine analog cyclocreatine (cCr). Loss and gain of function genetic approaches were used in combination with cCr therapy to define the contribution of CKB expression or creatine kinase activity to cell proliferation, migration, invasion, and metastasis in ER-negative breast cancers. Although tumor cell-intrinsic CKB was not essential for breast tumor cell proliferation or cell migration in vitro, CKB was necessary for cell invasion in vitro and strongly promoted tumor growth and metastasis in vivo. Similarly, cyclocreatine therapy repressed cell migration, cell invasion, formation of invadopodia, and lung metastasis. Moreover, in common TNBC cell line models, the addition of cCr to conventional agents, paclitaxel (Taxol) or doxorubicin, was either additive or synergistic to repress tumor cell growth.

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“…By regulating the cellular reservoir of high-energy phosphates [16], the Cr/PCr system actively drives the proliferation of tumor cells and the colonization of other tissues. Accordingly, the expression of CK, AGAT and CRT was induced in a variety of tumors, increasing intracellular Cr and ATP levels [162][163][164][165]. This energetic boost facilitates cancer cell division and survival [16,163,164,[166][167][168][169][170], and regulates metastasis by affecting cell motility and migration [161,164,165,170,171].…”

Section: Role Of Metabolism In Cancer Progression: Novel Insights From Creatine Modelsmentioning

confidence: 99%

“…Accordingly, the expression of CK, AGAT and CRT was induced in a variety of tumors, increasing intracellular Cr and ATP levels [162][163][164][165]. This energetic boost facilitates cancer cell division and survival [16,163,164,[166][167][168][169][170], and regulates metastasis by affecting cell motility and migration [161,164,165,170,171]. For instance, it has been shown that SLC6A8 overexpression promotes the proliferation and invasion of human tumor cells in vitro, whereas the knockdown of CRT suppresses these processes [164,170].…”

Section: Role Of Metabolism In Cancer Progression: Novel Insights From Creatine Modelsmentioning

confidence: 99%

“…In addition, Loo and colleagues found that exogenous PCr was sufficient to significantly enhance metastatization in animal models, whereas cancer cell lines depleted of the SLC6A8 gene displayed substantially reduced metastatic activity, even when CK was overexpressed [172]. A recent work also showed that, besides dietary Cr, endogenous synthesis plays a crucial role in metastases, as the knockdown of the AGAT gene in colorectal cancer cells significantly suppressed in vivo the invasion of the liver tissue, prolonging the life span of mice [165].…”

Section: Role Of Metabolism In Cancer Progression: Novel Insights From Creatine Modelsmentioning

confidence: 99%

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The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

Ghirardini

Calugi

Sagona

et al. 2021

Genes

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Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.

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Creatine promotes cancer metastasis through activation of Smad2/3

Cited by 83 publications

References 48 publications

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

HIF-dependent CKB expression promotes breast cancer metastasis, whereas cyclocreatine therapy impairs cellular invasion and improves chemotherapy efficacy

The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

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