Inhibition of breast cancer cell growth by methyl pyropheophenylchlorin photodynamic therapy is mediated though endoplasmic reticulum stress‐induced autophagy in vitro and vivo

Abstract

Autophagy and ER stress participated in the inhibition of MPPa‐PDT on tumor growth, but the molecular links between them remain undefined. We just explore the molecular mechanism between them in vitro and vivo. CCK‐8 assay and flow cytometer were used to detect the cytotoxicity and mode of cell death after MPPa‐PDT. Furthermore, the role of autophagy was verified in MPPa‐PDT. Confocal microscopy was used to show the intracellular distribution of MPPa. ER stress markers and PERK signaling pathway were detected by western blot. While in vivo, tumor histology and immunohistochemistry were performed to show the effect of MPPa‐PDT in mice. After MPPa‐PDT, cells viability decreased in dose‐dependent manner. Besides, the cell apoptosis increased along with the increasing of Beclin‐1and LC3B II but declining of P62. When pretreated with 3‐MA, LC3B II formation and the cytotoxicity declined. MPPa‐PDT caused increasing of ER stress markers (GRP78, CHOP) as MPPa accumulated in ER. However, pretreatment with ER stress inhibitor 4PBA, the expression of GRP78 and LC3B II was blocked but the PERK signaling pathway activated and the expression of P62 increased. In vivo, the tumor growth was significantly inhibited by MPPa‐PDT. Besides, the appearance of ER stress and autophagy was further demonstrated by immunohistochemistry. Our findings demonstrate that autophagy mediated by MPPa‐PDT was regulated by ER stress, via PERK signaling pathway, to kill MDA‐MB‐231 cells in vitro and vivo.

EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK‐eIF2α‐GRP94 and IRE1α‐XBP1‐GRP78

“…Autophagy is one of the mechanisms by which tumor cells escape death during starvation and drug treatments, and its inhibition increases the radiosensitivity of esophageal carcinoma cells . Activation of ERS induces autophagy in nerve cells . Therefore, we tested the role of EGFR and ERS signaling pathways on radiation‐induced autophagy and observed that EGFR knockdown downregulated the radiation‐induced expression of the autophagy marker protein LC3B and the related pathway protein Atg3, whereas salubrinal and tunicamycin reversed these effects partly (Figure B‐C).…”

“…Also, EGFR‐targeted therapy increased the radiosensitivity of non‐small cell lung cancer by inhibiting autophagy . Interestingly, ERS also induces autophagy . The regulation of radiosensitivity by autophagy is pleiotropic.…”

Cell death in photodynamic therapy: From oxidative stress to anti-tumor immunity

“…Furthermore, in vitro work confirmed PERK and eIF2α phosphorylation alongside CHOP and the BH3-only proteins (Bim and Noxa) consistent with the ER stress response [29,30]. PDT using other photosensitizers with ER tropism such as Rose Bengal [31], methyl pyropheophenylchlorin (3 1 ,3 2 -didehydrophytochlorin methyl ester) [32] and 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium (EtNBSe) [33] have also induced signs of ER stress, namely at the PERK-eIF2α axis. This was correlated with increased levels of GRP78/Bip and CHOP and caspase 12 dependent apoptosis.…”

MPPa-PDT suppresses breast tumor migration/invasion by inhibiting AKT-NF-κB-dependent MMP-9 expression via ROS

“…Pyropheophorbide-α methyl ester (MPPa), a derivative of chlorophyll (22), provides more advantages due to its better absorbance of and stronger permeability to PDT compared with first-generation photosensitizers. Our previous studies demonstrated that MPPa-PDT can inhibit breast cancer cell growth (23); however, the role of MPPa-PDT on invasion and migration in breast cancer is not clear. In the present study, we observed that MPPa-PDT inhibited breast cancer cell MCF-7 metastasis and the underlying molecular mechanisms, which may provide important implications for breast cancer treatment.…”