Potential mechanism of tumor growth suppression

Scientists at the Cold Spring Harbor Laboratory (New York State), working under the guidance of Professor Adrian Krainer, identified three molecular factors in tumor cells that stimulate the production of an enzyme involved in changing the carbohydrate metabolism of the cell. The metabolic status that develops as a result of this change, called the "Warburg effect", provides exceptionally rapid cell proliferation and tumor growth.

The main mediator of the effect discovered eight years ago by Nobel laureate Otto Warburg is the enzyme pyruvate kinase M2 (PK-M2). The second isoform of this enzyme, pyruvate kinase M1 (PK-M1), does not have such a pathogenic effect. In the article "The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism", published in the preliminary on-line version of the journal Proceedings of the National Academy of Sciences, the authors describe three factors contributing to an increase in the level of pyruvate kinase M2 in cancer cells, partly due to the suppression of the production of pyruvate kinase M1.

Compared to healthy cells, cancer cells consume much more glucose, but most of it is spent not on energy production, but on cell construction. A side effect of this process is the production of large amounts of lactic acid. Recently, researchers in the laboratory of Lewis Cantley from Harvard University have established that pyruvate kinase M2, which supports this alternative metabolic mechanism, is an important factor in the formation and growth of tumors.

This isoform of the enzyme is encoded by the same gene as its analogue pyruvate kinase M1, contained only in healthy cells, but is the product of alternative splicing of the enzyme-coding matrix RNA (mRNA). This molecular mechanism makes it possible to encode several proteins in one gene. The aim of the authors' work was to find mechanisms that switch the splicing process from the production of a normal version of the enzyme to the synthesis of its vicious analogue.

The study of the levels of various splicing factors in cells of different types of cancer narrowed the list of suspects to three proteins. All three identified factors are contained in high concentrations in tumor cells and inhibit the splicing of the harmless pyruvate kinase isoform, which, by default, triggers the production of pyruvate kinase M2.

Reducing the content of these factors in the cell restores the production of pyruvate kinase M1, while lowering the levels of pyruvate kinase M2 and lactic acid. However, scientists have yet to find out whether this effect is accompanied by a slowdown in the rapid growth of the tumor.

Blocking the activity of the three identified factors did not lead to a complete cessation of the production of pyruvate kinase M2, which indicates the possible existence of other factors affecting the ratio of synthesized enzyme isoforms. The authors are currently searching for these potential splicing regulators. They hope that eventually their efforts will lead to the identification of new therapeutic targets for cancer treatment.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru Based on ScienceDaily: Potential Way to Reverse Cancer Cell Metabolism and Tumor Growth.

26.01.2010