Protein Kinase B and Cancer

Protein Kinase B and Cancer: The Links

Protein Kinase B	Cell Cycle Regulation	Apoptosis
Glucose Metabolism		The Cancer Link

How is Protein Kinase B related to cancer? The answers lie in the biosignaling pathways it is involved in.

What is Protein Kinase B?

Protein Kinase B (also known as Akt, based on where it was originally identified) is a serine/threonine kinase, which controls key cellular processes including the cell cycle, cell death (apoptosis), and glucose metabolism through insulin . There is also evidence that PKB/Akt plays a role in cancer progression (West, K. A., et al. 2003). PKB is fully activated by phosphorylation at two sites, T308 and S473. Phosphorylation at one site produces a partially active protein and it seems that phosphorylation at each site is regulated separately. Activation normally occurs through upstream kinases such as PI-3-K (West, K. A., et al. 2003).

Figure 8. Some key downstream targets of PKB include GSK-3, p70s6K, 4EBP-1, and FKHR. These targets are responsible for promotion of the cell cycle, inhibition of apoptosis, and insulin signaling.

Cell Cycle/Cell Growth regulation:

PKB increases levels of MYC:

Figure 9. PKB can activate transcription factors such as MYC, which then go on to increase cyclin D levels, increase p27 degradation, and increase E2F activity, all of which promote the cell cycle and cell proliferation.

Protein Kinase B inhibits cell cycle arrest (ie-promotes cell cycle) in several ways:

- It phosphorylates p21 in the cytoplasm, preventing it from traveling into the nucleus where it causes cell cycle arrest. Without p21in the nucleus, some of the cell division checkpoints are inactivated and the cell can divide unchecked.

- It decreases p27 levels, promoting cell proliferation.

- It increases cyclin D levels, promoting cell proliferation.

- It maintains high levels of cyclin D1, also promoting cell division.

Cell death/apoptosis:

Protein Kinase B also inhibits cell death. Cells that no longer function properly are programmed to commit “suicide,” also known as apoptosis. This process can be triggered by DNA damage or other problems associated with the cell cycle. Some of the activating signals however, can be inhibited by PKB. If apoptosis is inhibited then cells have a greater chance of becoming cancerous.

PKB affects apoptosis by:

- Inactivating BAD (Fig. 10), a protein that promotes apoptosis.

- Inhibiting caspases, key executioners of apoptosis.

- Promoting angiogenesis (new blood vessel formation), a key requirement for cancer cell and tumor growth.

Figure 10. A survival signal (like nicotine) binds to its receptor (nAchR) and causes activation of PI 3-kinase, which then goes on to activate PKB through PDK1. Active PKB can inactivate BAD by phosphorylating it, in effect inhibiting apoptosis.

Glucose metabolism/insulin response:

PKB is involved in the body’s response to insulin and the utilization of glucose (Fig 11).

Figure 11. PKB is activated by PI-3K, and then goes on to inactivate GSK-3. This allows GS to be active, causing glycogen to be made. PKB also activates GluT4, which allows more glucose into the cell.

The Cancer Link

A reminder:

What can cause/promote cancer:
1. DNA damage
2. increased cell proliferation (inhibition of cell cycle checkpoints)
3. inhibition of cell death mechanisms
4. break of normal cell boundaries (invasion into other tissues)
A second reminder:

What Protein Kinase B can do:
1. increase cell proliferation by promoting the cell cycle
2. inhibit apoptosis

What carcinogens in cigarette smoke can do:
3. DNA damage

So the link is:
When you smoke a cigarette, the carcinogenic components (like NNK) cause DNA damage to your cells, which would normally cause them to arrest their cell cycles and perhaps undergo apoptosis. HOWEVER, the nicotine is absorbed into your bloodstream and activates protein kinase B, which promotes the cell cycle and inhibits apoptosis. So your cell’s normal machinery for preventing cancer is in effect turned off, and DNA damage is taking place (increasing the rate of mutations), providing an ideal situation for cancer to form.

Continue