Is Warburg Effect Determined by Embryonic Isoform of Pyruvate Kinase?

It has been more than 75 years since Dr. Otto Warburg disclosed the aerobic glycolysis in tumor cells around 1930. This metabolic phenomenon in tumors, seperating it from Kreb's cycle and anerobic fermentation, features high rates of glucose uptake, but low rates of oxidative phosphorylation, with production of lactic acid even in the presense of oxygen. The principles of aerobic glycolysis has been applied to fancy, popular approach to detect cancer recurrence sucha as PET (Positron Emission Tomography) in nuclear medicine contemporarily. Yet there are more to be explored, and potentially there may be more to be exploited in cancer treatment or prevention.

Christofk HR et al. published a paper on Nature last month which likns Warburg's observation to embryonic isoform of pyruvate kinase, M2. It has been known that cancer cells express embryonic M2 isoform of pyruvate kinase exclusively.

The authros first verified this exclusive expression of M2 isoform in cancer tissue by immunoblotting and immunohistochemistry. Then, using short hairpin RNA (shRNA) knockdown in H1299 cells (a human lung cancer cell line), plus rescue by mouse PKM1 (pyruvate kinase M1 isoform) and PKM2 (pyruvate kinase M2 isoform), they revealed that M2 isoform rescues more, in terms of glycolytic rate and replication. Moreover, M2 cells are mroe resistant to hypoxic circumstances, and mitochondrial ATP synthase inhibitor, oligomycin. Even more, ocygen consumption is lower in cells bearing M2 compensation, and lactate production is significantly higer. These findings succesfully connect M2 isoform of pyruvate kinase to Walburg's aerobic glycolysis as a determinant to escape tricarboxylic acid cycle and to enter the pathway for lactate production.

In the meantime, the authors also employed xenograft study on nude mouse by injecting H1299 tumor cells with M1 or M2 expression. This in vivo model resulted in bigger tumor, and more probablity to form tumors by lung cancer cell line bearing mouse M2 isoform vector.

I should say this is not intuitive, or even a violation of my current knowledge of biochemistry and glucose metabolism. Shouldn't the determining factors for entering citric cycle or lactic acid production lie after pyruvate? Are the end product of pyruvate by different isoform of pyruvate kinase different? Or, does pyruvate kinase act after pyruvate formation, and drive them into distinct destiny according to specific isoform? Or, doses the conformation of pyruvate kinase give it the ability to intervene the downstream reaction? (More spatial and temporal questions to be asked)

If we put aside these questions to clarify and make things consistent and focus on the applications, we may also ask how do cells switch from the adult M1 isoform of pyruvate kinase back to embronic M2 isoform? It is known that M2 isoform is a splice variant of M1, and how do we control than?

Although my questions may sound absurd, but I do take the authors' findings very seriously as an important breakthrough in cancer biology with great potential to further study, cancer treatment, and prevention.



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Tags: Medicine, Medicine-Oncology, Medicine-Cancer Biology, Medicine-Biochemistry, Medicine-Nuclear Medicine, Medicine-Biomedical Science, Medicine-Biological Science, Medicine-Bioscience, Dr. Otto Warburg, glycolysis, Aerobic glycolysis, citric cycle, citrate cycle, Kerb's cycle, TCA cycle, Tricarboxylic acid cycle, Anaerobic fermentation, Anaerobic glycolysis, Lactate cycle, Pyruvate, Pyruvate Kinase, Glucose metabolism, Cancer Cell metabolism, Pyruvate Kinase, M2 isoform, Embryonic isoform, Medicine-Developmental Biology, M1 isoform, Adult isoform, Immunoblotting, Immunohistochemistry, shRNA knockdown, hypoxia, mitochondrial ATP synthase, nude mouse, xenograft study, conformation change