CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer

Filippone, Maria Grazia; Gaglio, Daniela; Bonfanti, R; Tucci, Francesco; Ceccacci, Elena; Pennisi, Rosa; Bonanomi, Marcella; Jodice, Giovanna; Tillhon, Micol; Montani, Francesca; Bertalot, Giovanni; Freddi, Stefano; Vecchi, Manuela; Taglialatela, Angelo; Romanenghi, Mauro; Romeo, Francesco; Bianco, Nadia; Munzone, Elisabetta; Sanguedolce, Francesca; Vago, Gianluca; Viale, Giuseppe; Fiore, Pier Paolo Di; Minucci, Saverio; Alberghina, Lilia; Colleoni, Marco; Veronesi, Paolo; Tosoni, Daniela; Pece, Salvatore

doi:10.1038/s41467-022-30375-8

Cited by 19 publications

(15 citation statements)

References 55 publications

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“…More recently, it has been shown, in a preclinical study of patient-derived xenografts (PDXs) from CDK12HIGH and CDK12LOW human breast cancers, that CDK12 overexpression can predict response to metronomic methotrexate-based therapy. In addition, a retrospective analysis of lymph-node-positive breast cancer patients, randomized to receive metronomic cyclophosphamide plus methotrexate (CM) chemotherapy or no chemotherapy after completion of standard adjuvant treatments, confirmed CDK12 expression as a valuable biomarker in breast cancer patients [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Cazzaniga

Capici²,

Cordani

et al. 2022

JCM

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Metronomic chemotherapy (mCHT), defined as continuous administration of low-dose chemotherapeutic agents with no or short regular treatment-free intervals, was first introduced to the clinic in international guidelines in 2017, and, since then, has become one of the available strategies for the treatment of advanced breast cancer (ABC). Despite recent successes, many unsolved practical and theoretical issues remain to be addressed. The present review aims to identify the “lights and shadows” of mCHT in preclinical and clinical settings. In the preclinical setting, several findings indicate that one of the most noticeable effects of mCHT is on the tumor microenvironment, which, over the last twenty years, has been demonstrated to be pivotal in supporting tumor cell survival and proliferation. On the other hand, the direct effects on tumor cells have been less well-defined. In addition, critical items to be addressed are the lack of definition of an optimal biological dose (OBD), the method of administration of metronomic schedules, and the recognition and validation of predictive biomarkers. In the clinical context—where mCHT has mainly been used in a metastatic setting—low toxicity is the most well-recognised light of mCHT, whereas the type of study design, the absence of randomised trials and uncertainty in terms of doses and drugs remain among the shadows. In conclusion, growing evidence indicates that mCHT is a suitable treatment option for selected metastatic breast cancer (MBC) patients. Moreover, given its multimodal mechanisms of action, its addition to immunological and targeted therapies might represent a promising new approach to the treatment of MBC. More preclinical data are needed in this regard, which can only be obtained through support for translational research as the key link between basic science and patient care.

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Section: Resultsmentioning

confidence: 99%

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Cazzaniga

Capici²,

Cordani

et al. 2022

JCM

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“…Although overexpression of solute carrier family 27 member 6 inhibits NPC growth in vitro and in vivo, it enhances the metastatic ability of NPC cells (Zhong et al, 2022). Cyclin-dependent kinase 12 promotes tumorigenesis but induces vulnerability for breast cancer therapy via inhibiting folate one-carbon metabolism (Filippone et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

ZBTB7A governs 2-DG-inhibited glycolysis by regulating GLUT1 in nasopharyngeal carcinoma

LIU¹,

Wei²,

Lan³

et al. 2022

Biocell

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Our previous studies suggested a potential interaction between the POK erythroid myeloid ontogenic factor ZBTB7A and glucose transporter 1 (GLUT1) in nasopharyngeal carcinoma (NPC). This study was designed to confirm the interaction and further evaluate the precise mechanism by which ZBTB7A and GLUT1 regulate NPC development. The binding sites between ZBTB7A and the promoter of GLUT1 were predicted by bioinformatics.Gene expression was measured by quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunohistochemistry. The activities of key glycolysis enzymes, including hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), and lactate, were detected using specific enzyme-linked immunosorbent assay kits. The connection between ZBTB7A and GLUT1 was analyzed by dual-luciferase reporter assay and chromatin immunoprecipitation-qPCR. The vitality, proliferation, and tumorigenicity of the cells expressing different levels of ZBTB7A were tested by adding the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), followed by MTT, colorimetric focus forming, and xenograft assays, respectively. Our results showed that high expression of GLUT1 was associated with late-stage NPC. After constructing stably transfected cells with lentiviruses, ZBTB7A was effectively knocked down in 5-8F cells (RNAi-5-8F) and overexpressed in 6-10B cells (ZBTB7A-6-10B). The up-or downregulation of GLUT1 secondary to ZBTB7A changes was also limited. The vitality and proliferation of the cells expressing low ZBTB7A were notably blocked by 2-DG. The cells expressing high ZBTB7A were not very sensitive to 2-DG. The growth of RNAi-5-8F xenografts was strongly suppressed by 2-DG. The activities of HK, PK, and LDH were suppressed by 2-DG in the cells expressing low ZBTB7A. RNAi-5-8F cells had the lowest 2-DG-induced lactate production. ZBTB7A directly suppressed the promoter region of GLUT1 to regulate GLUT1 expression. Thus, ZBTB7A controls the 2-DG-induced inhibition of glycolysis by affecting GLUT1.

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“…Furthermore, intervention in the metabolism of serine and glycine was found to be an effective and less toxic method to improve the prognosis of patients with MYCN-amplified neuroblastoma ( 96 , 97 ). A recent clinical trial demonstrated that high CDK12 status could indicate a significant reduction in the distant metastasis rate of chemotherapy group and non-chemotherapy group, and integrative transcriptomic and metabolomic analysis revealed that the hyperactivation of serine-glycine-carbon network is an inherent metabolic feature of CDK12-induced tumors ( 98 ). Targeting the key enzymes in serine and glycine metabolism may be an effective treatment strategy.…”

Section: Serine and Glycine Metabolismmentioning

confidence: 99%

Amino acid metabolic reprogramming in tumor metastatic colonization

Wang

Chen

et al. 2023

Front. Oncol.

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Metastasis is considered as the major cause of cancer death. Cancer cells can be released from primary tumors into the circulation and then colonize in distant organs. How cancer cells acquire the ability to colonize in distant organs has always been the focus of tumor biology. To enable survival and growth in the new environment, metastases commonly reprogram their metabolic states and therefore display different metabolic properties and preferences compared with the primary lesions. For different microenvironments in various colonization sites, cancer cells must transfer to specific metabolic states to colonize in different distant organs, which provides the possibility of evaluating metastasis tendency by tumor metabolic states. Amino acids provide crucial precursors for many biosynthesis and play an essential role in cancer metastasis. Evidence has proved the hyperactivation of several amino acid biosynthetic pathways in metastatic cancer cells, including glutamine, serine, glycine, branched chain amino acids (BCAAs), proline, and asparagine metabolism. The reprogramming of amino acid metabolism can orchestrate energy supply, redox homeostasis, and other metabolism-associated pathways during cancer metastasis. Here, we review the role and function of amino acid metabolic reprogramming in cancer cells colonizing in common metastatic organs, including lung, liver, brain, peritoneum, and bone. In addition, we summarize the current biomarker identification and drug development of cancer metastasis under the amino acid metabolism reprogramming, and discuss the possibility and prospect of targeting organ-specific metastasis for cancer treatment.

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CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer

Cited by 19 publications

References 55 publications

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

ZBTB7A governs 2-DG-inhibited glycolysis by regulating GLUT1 in nasopharyngeal carcinoma

Amino acid metabolic reprogramming in tumor metastatic colonization

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