Pyruvate Kinase M, AMPK and Cancer

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Two important concepts in cancer research are pyruvate Kinase M (PKM) and AMP-activated protein kinase (AMPK). In particular, the isoform M2 of pyruvate kinase (PKM2) generates much interest. This is because of the potential roles it plays in inflammation. PKM2 is a regulator of metabolic alterations related to cancers.

Definition of Terms

We define important concepts:

  • Protein Kinase – is a kinase enzyme that changes other proteins by adding phosphates to them.
  • AMPK –is a protein kinase. It is a fuel-sensing enzyme present in mammalian cells. It is present in skeletal muscles, adipose tissue, brain and liver. AMPK is activated by exercise and other events that increase the ratio of AMP to ATP.
  • Pyruvate kinase (PK) – is a protein kinase involved in glycolysis. It facilitates the transfer of a phosphate group from PEP (phosphoenolpyruvate) to ADP (adenosine diphosphate). The process yields one ATP molecule and one pyruvate molecule.
  • PKM – refers to an M-isoform of pyruvate kinase. There are four pyruvate kinase isoforms: L (present in liver), R (erythrocytes), M1 (muscles, heart and brain) and M2 (fetal tissue and adult tissues). In this material, the two latter isoforms are referred as PKM1 and PKM2.

AMPK

AMPK was first studied as a regulator of fatty acid and cholesterol levels. In addition, it was also studied for its role in lipid metabolism. Consequently, it was also discovered that it also plays an important role in maintaining energy homeostasis in cells. This latter role made AMPK as an important energy metabolism regulating agent.

Activation of AMPK happens when energy at the cellular level is altered. The stimuli for AMPK activation are oxidation, hypoxia, ischemia, and glucose deprivation.

Once AMPK is activated, it sends phosphorus groups to several metabolic enzymes. When this happens, pathways that consume energy (ATP) are inhibited. As this happens, pathways that produce energy are activated. Examples of pathways that generate energy are fatty acid oxidation and glucose uptake.

AMPK and Cancer

One of the things that happen in cancer cases is that at the cellular level, normal energy processes malfunction. This is also described as a “dysegulation” of energy processes. AMPK activation is the mechanism that restores normal regulation of energy. By this mechanism, metabolic checkpoints are placed in pathways, resulting to inhibited cell growth. This is seen as a process that suppresses growth of metabolic tumors.

There is a huge literature showing the tumor suppressive role of AMPK, specifically in liver, colorectal and prostate cancers. May studies on other cancer types, such as melanoma and prostrate, are being conducted.

Here’s a look at what has been discovered so far for each type of cancer:

  • Lung cancer – AMPK activation in liver cancer cases results to better prognosis and survival. AMPK activity is higher in non-smoking patients than smoking patients.
  • Colorectal cancer – Studies suggests the possibility that AMPK activation benefits people with colon cancer. A relationship between activation of AMPK and survival still needs to be established.
  • Liver cancer – The liver plays an important function in lipid metabolism and oxidation of fatty acids. Liver diseases are often related with disorders in metabolism. Thus, AMPK function and the normal liver function are evidently linked. Studies suggest that AMPK activation seems to inhibit liver cancer cell growth by enhancing certain processes. These processes result to loss of the cells power to divide and grow and destruction of redundant cellular components.
  • Other cancers – Recent studies tackled the involvement of AMPK with melanoma, breast cancer, ovarian cancer, leukemia, and prostate cancer. In melanoma research, AMPK was shown to be important in regulating a protein necessary for normal development of melanocyte. In breast cancer cases, studies found diminished AMPK activity in 9 out of 10 cases. In leukemia, it has been found that AMPK activation may have therapeutic benefits.

Based on the investigations conducted, tumor suppressive effects of AMPK activation were observed. However, there are certain tumors and specific cellular contexts where this AMPK role was not observed. Further investigation is proposed.

Pyruvate Kinase

Pyruvate kinase (PK) is the catalyst involved in the final step of glycolysis. In glycolysis, ADP receives a phosphate group, a step that leads to the creation of pyruvate. Once pyruvate is synthesized, it joins the TCA (tricarboxylic acid) cycle. This leads to either ATP production or lactate formation.

The pyruvate kinase isoform PKM2 is the embryonic form of PK. It is present in cancer cells and in intestinal epithelial and lymphocyte cells. On the other hand, PKM1 is present in tissues that have high catabolic demands (muscle, heart and brain tissues).

PKM1 and PKM2 differ only by a few amino acids, but they have distinct functions. In studies, the isoform PKM2 is given more focus because it plays an important role in metabolic alterations distinct to inflammation and cancer.

In cancer cells, it has been observed that increased PKM2 expression allows production of certain substances such as glycine and serine. The force and changes that occur in the metabolic pathway in this process are crucial for the survival of cancer cells.

PKM2 and Cancer

Evidence suggests the idea that cancers primarily express PKM2. The enzyme is predominant in colon cancer lung cancer and renal cell carcinoma (RCC). Some suggest that PKM2 be used as an RCC marker. It was also suggested that it be made as a marker for testicular cancer as well.

Serum PKM2 levels are high in patients with gastrointestinal tumor, breast cancer, cervical cancer, lung carcinoma, urological tumors and colon cancer. PKM2 presence was also detected in the feces of colorectal and gastric cancer patients.

Mass spectrometry was recently used to confirm presence of PKM2 in cancer patients, and it showed predominant presence in RCC, follicular thyroid adenoma, lung carcinoma, colorectal cancer, liver carcinoma and bladder carcinoma.

Efforts are underway to target PKM2 as a therapeutic strategy for cancers. The ultimate goal for this is to target cancer metabolism. For these efforts, numerous PKM2 activators and inhibitors have been developed.

However, experts are cautious not to try knocking down PKM2 completely as it has been shown that the approach does not totally prevent cancer growth. Some see using small molecule activators to be a viable alternative.

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