Targeting the TGF-β-p21 axis: a critical regulator of bleomycin-induced cell cycle arrest and apoptosis in vitro-implication for progressive cervical cancer therapy

Cervical cancer signifies a global health concern and is a major cause of cancer mortality in women worldwide. Dysregulation of apoptotic pathway and cell cycle play a role in cancer development. Aberrant signalling pathways leads to complex mechanisms leading to the severity. Bleomycin is an anti-tumor glycopeptide molecule which exhibits impressive cytotoxicity in cancer cells. However, its modulating significance on TGF-beta induced cell cycle arrest and apoptosis in cervical cancer remains elusive. We confirmed the cytotoxicity, anti proliferative effect of bleomycin in HeLa cells. Meanwhile, bleomycin also led to the suppression of cell migration, invasion. Relative gene expression quantification for cell cycle regulatory, apoptotic, and TGF-beta member's genes was done by qRT-PCR. Bleomycin markedly downregulated the expression of cyclin A2, cyclin B1 and cell cycle arrest at G2/M phase in vitro. Dual AO/EB and Propidium iodide staining was done to evaluate early and late apoptosis in cervical cancer cells. Bleomycin prompts early and late apoptosis in cervical cancer cells by chromatin condensation and blebbing. Mechanistically, bleomycin activates TGF-beta induced p21 cascade by upregulation of GADD45A and GDF11, stabilizing p53, to induce cell cycle arrest and apoptosis. Bleomycin induces DNA damage triggering TGF-beta pathway. This study can broaden our understanding of the signalling mechanisms that could develop effective strategies for cancer therapy. Elucidation of these pathways in cervical cancer may ultimately lead to novel and more effective treatments. Here, we highlight apoptosis-inducing drug as a therapeutic strategy to regulate the process of carcinogenesis, and regulating apoptosis could benefit cancer treatment and prevention.