Cyclin and CDK Regulation in Cell Cycle Progression and Cancer Treatment

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Introduction

Several growth-related processes, the most noteworthy of which is the cell cycle checkpoint, involve two classes of proteins that include the cyclins and cyclin-dependent kinases, or CDKs. Cyclins are identified as regulatory proteins that can positively control the activity of CDKs; these cyclin-CDK complexes are involved in directing the cell through different phases of the cell division process and genetic replication. Cyclin-CDK is crucial for progress through the cell cycle, and alteration of this cycle can be seen as a characteristic of cancer. Problems in the cyclin-CDK pathways, for example, overexpression of cyclins or mutations of CDKs, are frequent in cancer cells, which leads to their use as therapeutic targets. knowledge has been discovered on how to modulate these proteins for use in cancer, and there are several therapeutic approaches being actively pursued targeting the aberrant cyclin-CDK complexes. To that end, we sought to explore an understanding of the regulatory functions of cyclins and CDKs, the association of their dysregulation with cancer development, and how current developments in the management of cyclin and CDK dysregulation are being addressed.

Understanding Cyclins and CDKs in Cell Cycle Regulation

Cyclins and CDKs together create a checkpoint-based control system that allows the cell to progress smoothly through the cell cycle phases: G1, PLUS (duct DNA synthesis), G2, AND M (mitosis). Downstream processes are activated or inhibited by a distinct set of cyclin-CDK complexes, controlling how far down a pathway each phase should go. While CDKs are relatively stable throughout the process, the cyclins change levels in response to both internal and external signals, activating the kinase only when needed. This is because cyclin proteins are required to highly oscillate concerning their accumulation and degradation, programming the cell to pass through DNA replication, repair, and division at precise times.

Cyclin D is part of a CDK4/CDK6 complex with which it associates in early G1, able to form complexes capable of phosphorylating the retinoblastoma protein (RB), a tumor suppressor that keeps cells from entering the cell cycle until it is deactivated. RB gets released by phosphorylation, which then releases them from the transcription factor E2F, so transcription of genes requires DNA synthesis and transition of the cell into the next stage of the S phase. Where cyclin E then activates CDK2, and so the cell goes from the late G1 to the S phase. CDKs that control DNA synthesis (cyc; A binding to CDK2) during S phase and mitosis (cyc; A and cycB binding to CDK1) are linked. Controlled cyclin-CDK pair action guarantees order cell cycle progression and prevents aberrant cell division.

Cyclin and CDK Dysregulation in Cancer

Cyclins and CDKs are precisely regulated in healthy cells to maintain equilibrium between cell proliferation and arrest. But in cancers, this balance is unbalanced because often cyclins are overexpressed or amplified, and mutations in CDKs or mutations in CDK inhibitors (CKIs) like p21 and p27.    For example, cyclin D and E overexpression is seen in quite a few cancers, as well as inappropriate activation of CDKs and uncontrolled cell proliferation. Cyclin D or CDK4/6 overactivity leads to producing an RB that is no longer tightly phosphorylated around E2F activation, resulting in continual E2F activation and unregulated cell cycle entry, contributing to many tumors.

CKI also plays an important role in cancer biology as well. Normally, CKIs like p21 and p27 are brakes on CDKs, putting the brakes on CDK activity in response to cellular stress or DNA damage, so that cannot divide when its cells are damaged. Nevertheless, in some cancers, CKIs are either mutated or functionally inactivated and thus unable to suppress CDK activity. As an example, in several cancers that lack functional p53 (a tumor suppressor protein that upstream regulates p21), CDK inhibition fails, allowing the cell cycle to progress even though the cells are damaged. One common theme underlying the loss of CKI function in malignancies is the elimination of important regulatory checkpoints by p27 degradation or p21 repression to permit cancer cells to proliferate under conditions that should normally have suppressed cell cycle progression.

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The Role of Cyclin-CDK Complexes in Tumor Development

Extensive studies of the connection between cyclin-CDK complexes and cancer have been conducted to learn what specific alterations are responsible for various types of cancer. Cyclin D-CDK4/6, cyclin E-CDK2, and cyclin A-CDK2 complexes are frequently involved in tumorigenesis. The Cyclin D-CDK4/6 complex is a major regulator of the G1/S transition, phosphorylating RB to initiate a cascade of transcriptional events required for DNA replication. The hallmark of these cancers is abnormal activation of this complex by either cyclin D overexpression or CDK4 mutation.

In addition, other proteins bound to these complexes, including the DREAM complex and E2F transcription factors, also promote cancer. The p130-bound DREAM complex (p130, E2F4, MuvB core) is necessary for gene repression and has a vital function in cell cycle arrest. During the G0 and early G1 phases, they bind the E2F promoters and prevent cell division at an unscheduled period. But cancer cells often shut down this control, shutting down the p53-DREAM pathway, and letting unchecked cell proliferation run wild. When released from RB, E2F transcription factors activate genes needed for S phase entry. A third mechanism cancer cells often use to subvert the RB pathway is by enabling the uncontrolled transcription of key genes required for tumor growth and survival by promoting E2F activity because RB is disabled.

Targeting Cyclin-CDK Pathways in Cancer Treatment

Cyclins and CDKs play a central role in cell cycle regulation and are therefore promising therapeutic targets. However, CDK inhibitors, particularly those targeting CDK4/6, have had outstanding success in preclinical and clinical studies, most dramatically in breast cancer. Palbociclib, ribociclib, and abemaciclib inhibit CDK4/6 by blocking the CDK4/6-cyclin D complex and preventing RB phosphorylation and cell cycle arrest in the G1/S checkpoint. In hormone receptor-positive and HER2-negative breast cancers, these inhibitors are used in combination with endocrine therapy to improve treatment outcomes and are especially effective; these inhibitors are most important.

In parallel to the development of CDK inhibitors directed against CDK4/6, research has been conducted on inhibitors targeting CDK2, CDK7, and CDK9. These cyclin E-overexpressing cancers are potential candidates for CDK2 inhibitors. Transcriptional regulation is a focus of CDK7 and CDK9 inhibitors since these CDKs are responsible for the activity of RNA polymerase II and transcriptional elongation. For example, disabling the CDK9 can curtail the translation of antiapoptotic proteins in cancer cells, making them more vulnerable to chemotherapy and leading to cell death. These novel CDK inhibitors are currently in clinical development in multiple cancers, including lung, liver, and hematological malignancies.

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Challenges and Future Directions in CDK Inhibition Therapy

The CDK inhibitors have been promising, but there remain challenges. This is particularly true; one major obstacle to developing resistance to CDK inhibition is that cancer cells learn to live despite the treatment. Resistance mechanisms include overamplification of cyclin E, mutations in RB, and the activation of alternative pathways that bypass CD inhibition,  such as the overactivation of an AKT signaling. For this reason, a need exists for combination therapies that identify and target both cyclin-CDK activity and other complementary pathways. A good example of this is the investigation of combining CDK4/6 inhibitors with PI3K or AKT inhibitors to improve efficacy and avoid resistance in cancer treatment.

Complementing that, there has been interest in the role of CDK inhibitors in modulating the immune environment. More recently, studies demonstrating that CDK4/6 inhibition improves anti-tumor immunity by increasing T cell infiltration and altering immune checkpoint proteins have arisen. With this, new roads to take CDK inhibitors together with antibodies for immune checkpoint inhibitors like PD-1 and PD-L1 have been opened and are creating a more powerful immune response against cancer.

With the increasing appreciation for the subtlety of cyclin-CDK interactions, new opportunities for cancer therapy are created. Advances in proteomics and high-throughput screening have enabled researchers to identify specific cyclin-CDK regulatory mechanisms in individual cancers, leading to an exciting opportunity for the development of personalized CDK inhibitor therapies. Moreover, new targets in terms of biochemical interactions between cyclins, CDKs, and other cell cycle regulatory proteins are found, and the understanding of the biology of cancer is improved by continued research on this topic.

Conclusion

To summarize this comprehensive analysis in conclusion, cyclins and CDKs are involved in cell cycle progression regulation that is critical for cellular processes and one of the major studies in cancer-affected cells. The cyclin-CDK pathways are deregulated in a great number of cancer cells, helping stratify the constant division process and warranting these proteins as prospective effective anti-cancer drug targets. Regarding the approved CDK inhibitors, positive results have been obtained, especially in the treatment of breast cancer, but treatment resistance and proper drug combinations are still among the key challenges to address. CCDK inhibition therapy in the future will bring a breakthrough in cancer treatment, improving patient outcomes considerably by enabling the selective targeting of tumor cells-based individualized oncology based on the alteration profile of each tumor.

References

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