Gramine Suppresses Cervical Cancer by Targeting CDK2: Integrated Omics-Pharmacology and In Vitro Evidence

TL;DR

Gramine, a plant-derived compound, may help treat cervical cancer by targeting CDK2 and affecting cell growth and immune responses.

Contribution

This study reveals a novel mechanism by which Gramine suppresses cervical cancer via a ceRNA axis involving CDK2 and immune-related molecules.

Findings

Gramine inhibits cervical cancer cell proliferation and migration while inducing apoptosis.

CDK2 is identified as a key target of Gramine, with reduced mRNA and protein levels after treatment.

The CYP4A22-AS1/LINC00958–hsa-miR-133b–CDK2 ceRNA axis is implicated in Gramine's anti-cancer effects.

Abstract

Cervical cancer (CC) remains a common malignant tumor that seriously threatens women’s health globally. Gramine (GR), a natural alkaloid derived from plants such as Arundo donax L., exhibits anti-tumor activities, yet its mechanistic actions in CC are still unclear. Here, we integrated cell-based assays, network pharmacology, and multi-omics analysis to systematically investigate the molecular mechanisms underlying GR’s anti-CC effects. In vitro experiments showed that GR significantly inhibited proliferation and migration, induced apoptosis, and triggered G0/G1 phase cell cycle arrest in HeLa cells. Integrated multi-omics analysis identified CDK2 as a critical target of GR, with both mRNA and protein levels markedly reduced following treatment. Mechanistically, GR likely suppresses CC progression by modulating the “CYP4A22-AS1/LINC00958–hsa-miR-133b–CDK2” competitive endogenous RNA (ceRNA) axis. Immune analysis indicated positive correlations of CDK2, CYP4A22-AS1, and LINC00958 with the immune checkpoint molecule CD47. Collectively, our findings demonstrate that GR inhibits CC through a ncRNA-mediated suppression of CDK2, leading to reduced HeLa cell proliferation and migration and enhanced apoptosis. These results provide a mechanistic rationale for developing GR as a candidate agent for targeted therapy and immuno-combination strategies in CC.

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