An increase in the incidence and mortality rate of cancer has been noted worldwide, especially for lung cancer. Many patients with lung carcinoma harbor mutations in epidermal growth factor receptor (EGFR), and initially show a good response to molecular target drugs, such as gefitinib, which inhibits the EGFR tyrosine kinase. However, recurrence inevitably occurs within a few years because of acquired drug resistance, leading to poor prognosis. Despite the development of new generations of molecular targeted drugs, recurrence and acquired drug resistance remain problematic. Emerging evidence suggests that cancer stem-cells (CSCs) are responsible for tumor recurrence and drug resistance. Tumor tissues comprise heterogeneous cell types including CSCs and their differentiated progeny, as observed in normal tissues derived from tissue-specific stem cells. Examples of tumors with CSCs are colorectal and lung cancers. Most antitumor therapies, such as conventional chemotherapy, radiotherapy and molecular target drugs, target rapidly proliferating differentiated cancer cells, but not CSCs. It is thought that cancer cells with stem-like properties continue to survive after treatment, and a fraction of these cells exhibit the ability to re-divide after years, causing recurrence.
Thus, targeted therapies against CSCs and their daughter cells are important for tumor eradication; however, this is still an area of unmet medical need. To establish such therapies, it is important to investigate the molecular mechanisms that determine how CSCs are maintained in cancer tissues. Although it is believed that various metabolic pathways are activated in cancer cells, the specific metabolic mechanisms in CSCs remain largely unclear. One-carbon (1C) metabolism incorporates carbons as building blocks of purine and pyrimidine that are used for DNA replication and RNA transcription, and thus plays an important role in cell proliferation. In the mitochondria, methylene-tetrahydrofolate dehydrogenase (MTHFD2), an enzyme involved in 1C metabolism, is strongly expressed in cancer cells, while it is scarcely expressed in normal cells. MTHFD2 is required for cancer cell proliferation as participate to DNA synthesis. Active MTHFD2 consumes 5-aminoimidazole carboxamide ribonucleotide (AICAR), an intermediate of the purine synthesis pathway, to produce IMP, a purine nucleotide immediate precursor. This way cancer cells get rid of AICAR excess. And for a good reason.
Like AMP, AICAR is a direct activator of AMP-dependent protein kinase (AMPK-alpha), an energy sensor that is also involved in growth arrest. Fifteen years ago, the tumor suppressor liver kinase B1 (LKB1) was found to be the main upstream kinase of AMPK, implying that the tumor suppressor effects of LKB1 may be mediated by AMPK. Since then, AMPK-regulating drugs have been studied in vitro and in vivo to analyze the role of AMPK in carcinogenesis and progression of cancer. AICAR can regulate cellular energy metabolism and induces mitochondrial proliferation and apoptosis. It has been demonstrated that AICAR has anti-cancer effects in many cancers. Part of this action is exerted through inhibition of protein synthesis. The ability of AMPK to inhibit protein synthesis is mediated in large part by direct inhibition of the mTORC1 complex. mTOR is a central integrator of nutrient and growth factor signals that activates many biosynthetic pathways, while stimulates cellular division. A team of japanese scientists from Kanazawa University discovered that it is essential to continuously consume AICAR and reduce its concentration in cancer cells to low levels for the maintenance of CSCs.
Active MTHFD2 is critical for this mechanism. Therefore, MTHFD2-mediated mitochondrial C1metabolism appears critical for the survival of CSCs and resistance to drugs including gefitinib through consumption of AICAR, leading to depletion of the intracellular pool of AICAR. Because CSCs are dependent on MTHFD2, therapies targeting MTHFD2 may eradicate tumors and prevent recurrence. And research is already started. The same team has already published preliminary data about an in-silico screening that identified three putative MTHFD2 inhibitors from a set of half a million of molecules. Other result suggested that suppression of MTHFD2 is an important target for cancer therapy in colorectal cancer and lung cancer. Other than MTHFD2, scientists also investigated TYMS, an enzyme involved in C1 metabolism and a target of 5-fluorouracil. TYMS expression was not related to overall survival of colorectal cancer or lung cancer patients, suggesting that MTHFD2 has a greater effect on prognosis than TYMS. These results highlight MTHFD2 inhibitors as a promising therapy for colorectal cancer and lung cancer.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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