Verteporfin Is a Promising Anti-Tumor Agent for Cervical Carcinoma by Targeting Endoplasmic Reticulum Stress Pathway

Abstract

Accumulated evidence has shown that the photosensitizer Verteporfin (VP) may be an ideal agent for various cancer types. However, the effect and mechanism of VP on human cervical carcinoma remain rudimentary. The aim of this study was to investigate the effect of VP on human cervical carcinoma cells (HeLa and SiHa cells) and to elucidate the possible mechanism. CCK-8, wound healing assay, flow cytometry analysis, western blotting, TUNEL staining were performed to evaluate the effects of VP on HeLa and SiHa cells in vitro as well as in vivo on a xenograft model. In addition, the role of endoplasmic reticulum (ER) stress in VP-induced apoptosis was investigated using RT-qPCR and western blotting. The results showed that the viability of HeLa and SiHa cells was suppressed by VP in dose-and time-dependent manners. Compared with the control group, apoptosis rates were higher with stronger TUNEL fluorescence signals in the experimental group, which substantiated that VP induced apoptosis at both 2D and 3D cell levels. Besides, VP can squelch the growth of tumors in both sizes and weights on the xenograft models without impairing ovarian reserve. Mechanism studies demonstrated that VP activated ER stress by upregulating the expression of GRP78, CHOP, and Caspase-12, and VP-induced apoptosis can be alleviated when ER stress pathway was inhibited. Our results provided a foundation for repurposing VP as a promising agent for cervical cancer patients without obvious reproductive toxicity by targeting ER stress pathway, and more researches are required to support its application in clinical practice.

Induction of apoptosis using ATN as a novel Yes‐associated protein inhibitor in human oral squamous cell carcinoma cells

“…YAP silencing increased cisplatin sensitivity through the inactivation of PI3K/Akt signaling in hepatocellular carcinoma cells 43 . Verteporfin promoted apoptosis in cervical cancer cells through caspase‐3 and endoplasmic reticulum stress activation 44 . In the present study, ATN, a YAP inhibitor, suppressed cell growth by modulating caspase‐dependent apoptosis in OSCC cells.…”

“…43 Verteporfin promoted apoptosis in cervical cancer cells through caspase-3 and endoplasmic reticulum stress activation. 44 In the present study, ATN, a YAP inhibitor, suppressed cell growth by modulating caspase-dependent apoptosis in OSCC cells. We also During the initiation of cancer metastasis, EMT is an essential step that leads to the loss of cell-cell junctions, morphological changes, and cytoskeletal remodeling.…”

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress

“…Although VPF treatment was previously found to cause ER stress (Wang et al, 2020), here we have connected the derepression of DDIT4 by YAP-TEAD inhibition to the reduced mTOR function and subsequent impairment of ER biogenesis.…”

ARID1A-mutated cervical cancer depends on the activation of YAP signaling

“…This approach provides a promising future in precision medicine since it is based on ARID1A mutational status and the mutual exclusivity of ARID1A mutations and YAP amplification. The YAP signaling inhibitor, verteporfin, is an ideal agent for various cancer types [36]. Notably, more effort is warranted to interrogate the potential of verteporfin in the clinical trials of cervical cancer.…”