Verteporfin Imparts Cell Cycle Arrest and Induces Apoptotic Machinery in TNBC Cells Through Sabotaging YAP Transactivation

Sulfath Thottungal Parambil,Gisha Rose Antony, Ajeesh Babu Littleflower, Lakshmi S

crossref(2022)

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摘要
Abstract Triple-negative breast cancer (TNBC) subtype endows distinctive biological features including aberrant proliferation, deducing the molecular mechanism harmonizing the TNBC characteristics is crucial for the greater understanding and prognosis of the disease. The aim of the present study was to analyze the anti-tumorigenic effects of Verteporfin (VP) in TNBC in vitro. We evaluated the tumorigenic properties of TNBC cells upon verteporfin treatment to assess the cell viability, apoptosis, cell cycle, cell survival, and protein/mRNA expressions in MDA-MB-231 and SUM-159 breast cancer cells. Transient silencing of YAP was performed to validate the data. TNBC cells exhibited a comparatively higher active YAP downstream signaling and VP resulted in the nuclear exclusion of YAP to a significant extent. Verteporfin inhibits the proliferation of TNBC cells by altering cyclin-dependent kinase inhibitors, thereby rendering cellular arrest at the G0/G1 phase. In a dose-dependent manner, verteporfin induces the apoptotic machinery in TNBC cells. Moreover, transient silencing of YAP in TNBC cells exhibited a similar pattern of anti-proliferative effects. Elevated YAP nuclear activity and downstream signaling in TNBC is associated with sustaining the proliferative capacity of the cells by inhibiting the cellular apoptosis. Verteporfin induces anti-proliferative effects on TNBC via cytoplasmic retention of YAP. Consequently, cells rewire the course of the cell cycle and stimulate cellular death. We suggest YAP signaling as a prerequisite for the TNBC cell progression and verteporfin without light activation exerts anti-tumorigenic effects on TNBC cells.
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