Reviving p18INK4c: Harnessing a tumor suppressor for cancer treatment

Cancer is marked by unchecked cell growth and proliferation, typically resulting from disruptions in the cell cycle. Central to this process are cyclins and cyclin-dependent kinases (CDKs), which regulate cell division. Overactivation of CDK-cyclin complexes is commonly observed in cancer, leading to the development of CDK inhibitors (CDKIs) as therapeutic agents. Among these, p18INK4c, a key member of the INK4 family, a group of cyclin-dependent kinase inhibitors that regulate cell cycle progression by inhibiting CDK4/6 activity, plays a critical role in maintaining cell cycle homeostasis. By inhibiting CDK4 and CDK6, p18INK4c prevents phosphorylation of the retinoblastoma protein (Rb), inducing cell cycle arrest and inhibiting cancer cell proliferation. Dysregulation of p18INK4c expression is observed across several cancers, strongly supporting its role as a tumor suppressor. This review explores the therapeutic potential of restoring p18INK4c function in cancer treatment. We analyze the molecular mechanisms by which p18INK4c regulates the cell cycle and how its dysregulation promotes cancer progression. Additionally, we highlight potential strategies aimed at enhancing p18INK4c activity, underscoring its promise as a target for reactivating tumor-suppressive pathways in cancer therapy.