S-phase kinase-associated protein 2, or Skp2, is a protein involved in the fundamental processes of cell growth and division. Its functions are connected to the orderly progression of a cell’s life, ensuring that cellular activities proceed in a controlled manner. Because it governs cell proliferation, Skp2 is studied for its influence on both normal tissue maintenance and the development of diseases.
Understanding Skp2’s Function in Healthy Cells
In a healthy cell, Skp2 is a component of a larger assembly known as the SCF ubiquitin ligase complex. This complex acts as a molecular machine that identifies and tags other proteins for disposal. Skp2’s role is to find and bind to specific target proteins scheduled for degradation by the cell’s waste disposal system, the proteasome.
The timing of Skp2’s presence is tightly controlled throughout the cell cycle. Its levels are low when a cell is in a resting state (G0/G1 phase) but rise as the cell prepares to duplicate its DNA. The amount of Skp2 peaks during the DNA synthesis (S) and subsequent growth (G2) phases, before declining as the cell divides. This fluctuation dictates the activity of the SCF complex.
One of the most well-documented targets of Skp2 is a protein called p27Kip1, or p27. The p27 protein functions as a brake on the cell cycle, preventing it from advancing from the G1 phase into the S phase. By tagging p27 for destruction, Skp2 effectively releases this brake, allowing the cell to move forward and replicate its genetic material.
This regulated destruction of proteins like p27 is part of normal cell proliferation, required for tissue repair. When Skp2 targets p27, it initiates a cascade that allows other proteins, called cyclin-dependent kinases, to become active and drive the cell cycle forward. This control over Skp2 ensures that cells divide only when necessary, maintaining tissue integrity.
The Role of Skp2 in Cancer Progression
The transition from a healthy to a cancerous cell often involves the breakdown of systems that control cell growth. Skp2 is frequently identified as a contributor to this malignant transformation. Studies have revealed that Skp2 is overexpressed, or found in abnormally high quantities, in many human cancers, which disrupts the balance of cell cycle control.
When Skp2 levels are excessively high, its activity becomes deregulated, leading to the accelerated degradation of its target proteins. The most significant consequence is the excessive destruction of tumor suppressor proteins like p27. With p27 levels diminished, the brakes on the cell cycle are effectively removed, leading to uncontrolled cell proliferation, a hallmark of cancer.
The link between high Skp2 levels and cancer has been shown to be a factor in patient prognosis. For instance, in oral epithelial carcinoma, elevated Skp2 expression is associated with the progression to invasive cancer and often corresponds with reduced p27 levels. Similar patterns are observed in various hematological malignancies, including leukemia and lymphoma, where increased Skp2 is linked to tumor progression.
Beyond promoting proliferation, Skp2’s activity is implicated in other aspects of cancer progression, such as enhancing the properties of cancer stem cells. These cells are a subpopulation within a tumor thought to be responsible for tumor initiation, chemoresistance, and relapse. In models of osteosarcoma and prostate cancer, Skp2 activity has been shown to maintain these aggressive, self-renewing cell populations.
Therapeutic Strategies Targeting Skp2
Given its involvement in promoting uncontrolled cell growth, Skp2 has emerged as a target for cancer therapy. The rationale is that blocking Skp2’s function could restore the levels of tumor suppressor proteins like p27, halting the proliferation of cancer cells. Researchers are exploring several strategies, with a primary focus on developing drugs that can inhibit Skp2’s activity.
The main avenue of investigation is the development of small-molecule inhibitors. These compounds are designed to interfere with Skp2’s function, either by blocking its ability to bind to substrates like p27 or by preventing its incorporation into the SCF complex. By disrupting this interaction, the inhibitors prevent p27’s degradation, allowing it to accumulate and reimpose its braking effect on the cell cycle. Preclinical studies using such inhibitors have shown promise in various cancer models.
For example, in studies on osteosarcoma, small-molecule Skp2 inhibitors were found to promote cancer cell death (apoptosis), arrest the cell cycle, and inhibit cancer stem cells. These inhibitors showed effectiveness on their own and demonstrated synergy when combined with conventional chemotherapy. This suggests that targeting Skp2 could help overcome the resistance that tumors often develop to standard treatments.
Despite promising developments, creating Skp2-targeted therapies presents challenges. One hurdle is ensuring the inhibitor is highly specific to Skp2 to avoid disrupting other cellular processes and causing side effects. The development of resistance to these new drugs is another issue researchers must consider. The continued exploration of Skp2 inhibitors represents a targeted approach that could offer new options for patients with cancers characterized by Skp2 overexpression.