The Pim-3 proto-oncogene is a significant area of focus in cancer research, representing a potential avenue for new therapeutic strategies. This gene produces a protein known as Pim-3, which acts as a serine/threonine kinase. Kinases are like molecular switches within cells, responsible for adding phosphate groups to other proteins, thereby turning their activity on or off.
Pim-3 belongs to a small family of related proteins, including Pim-1 and Pim-2, all of which share similar functional characteristics. The classification of Pim-3 as a “proto-oncogene” indicates that it is a normal gene found in healthy cells. However, if this gene undergoes specific alterations or is produced in excessively high amounts, it holds the potential to contribute to the development of cancer.
Pim-3’s Role in Cellular Processes
In healthy cells, Pim-3 performs several biological functions that maintain cellular balance. One of its roles involves promoting cell survival by helping to prevent a process called apoptosis, which is programmed cell death. Apoptosis is a natural and controlled mechanism for removing damaged or unnecessary cells, ensuring the integrity of tissues. Pim-3 contributes to this by phosphorylating specific pro-apoptotic molecules like BAD, which then prevents them from triggering cell death pathways.
Pim-3 also plays a part in regulating the cell cycle, which is the sequence of events that cells go through as they grow and divide. By influencing this cycle, Pim-3 helps ensure that cells progress through their stages of division in an orderly manner, supporting proper tissue growth and development. Its activity contributes to the controlled proliferation of healthy cells.
Pim-3 influences cell metabolism, assisting cells in managing their energy resources and nutrient utilization. This includes its involvement in regulating the activity of AMPK, a protein that plays a role in cellular energy balance.
The Connection Between Pim-3 and Cancer
While Pim-3 performs normal functions in healthy cells, its dysregulation is problematic in cancer. Overexpression of Pim-3 is common, meaning cancer cells produce far greater quantities of this protein than normal cells. This excessive production transforms Pim-3 into an active driver of cancerous growth and progression.
Pim-3 overexpression contributes to uncontrolled tumor growth. By promoting cell cycle progression and preventing apoptosis, Pim-3 allows cancer cells to divide continuously, leading to tumor formation. Its anti-apoptotic function helps cancer cells evade natural death signals.
Pim-3 contributes to cancer progression by influencing metastasis. It promotes cell migration and invasion, assisting cancer cells in breaking away from a primary tumor and establishing new growths elsewhere. For instance, in hepatoblastoma, Pim-3 overexpression has been shown to increase the phosphorylation and cell surface expression of CXCR4, a key receptor involved in cancer cell metastasis, allowing cancer cells to move more readily into secondary organs.
Pim-3 overexpression also contributes to therapy resistance. High levels of Pim-3 can make cancer cells less responsive to conventional treatments like chemotherapy and radiation. This occurs because Pim-3 activates signaling pathways that bolster cancer cell survival, making them resilient to therapy. Targeting Pim-3 is thus an attractive strategy to overcome this resistance and improve treatment outcomes.
Developing Pim-3 Inhibitors for Treatment
Given Pim-3’s role in driving cancer growth and resistance, it has emerged as a promising target for new anti-cancer drugs. A Pim-3 inhibitor is a type of drug specifically designed to block the activity of the Pim-3 protein. By interfering with Pim-3’s function, these inhibitors aim to disrupt the cancer-promoting pathways it activates, thereby hindering tumor growth and enhancing the effectiveness of other therapies.
Researchers are actively developing Pim-3 inhibitors, with many candidates in preclinical or early clinical trial phases. These inhibitors aim to bind to and inactivate Pim-3, preventing it from phosphorylating target proteins. This approach holds promise because inhibiting Pim-3 has been shown to reduce cell proliferation and tumor growth in laboratory and animal models of various cancers, including those of the liver, pancreas, colon, stomach, and breast.
A challenge for researchers is designing inhibitors highly specific to Pim-3, avoiding effects on its related family members, Pim-1 and Pim-2. While pan-Pim inhibitors (which target all three isoforms) have entered early clinical trials, they have sometimes faced challenges with potency, specificity, or side effects, such as cardiotoxicity. Developing more selective Pim-3 inhibitors could minimize off-target effects and lead to more effective and safer treatments for patients with Pim-3-driven cancers.