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Genetic Aberrations Associated with Photodynamic Therapy in Colorectal Cancer Cells.

ABSTRACT: Photodynamic therapy (PDT) is a cancer treatment modality that utilizes three components: light (? 650-750 nm), a photosensitizer (PS) and molecular oxygen, which upon activation renders the modality effective. Colorectal cancer has one of the highest incident rates as well as a high mortality rate worldwide. In this study, a zinc (Zn) metal-based phthalocyanine (ZnPcSmix) PS was used to determine its efficacy for the treatment of colon adenocarcinoma cells (DLD-1 and Caco-2). Photoactivation of the PS was achieved by laser irradiation at a wavelength of 680 nm. Dose responses were performed to establish optimal PS concentration and irradiation fluence. A working combination of 20 µM ZnPcSmix and 5 J/cm2 was used. Biochemical responses were determined after 1 or 24 h incubation post-treatment. Since ZnPcSmix is localized in lysosomes and mitochondria, mitochondrial destabilization analysis was performed monitoring mitochondrial membrane potential (MMP). Cytosolic acidification was determined measuring hydrogen peroxide (H2O2) levels in the cytoplasm. Having established apoptotic cell death induction, an apoptosis PCR array was performed to establish the apoptotic mechanism. In DLD-1 cells, expression of genes included 3 up-regulated and 20 down-regulated genes while in Caco-2 cells, there were 16 up-regulated and 22 down-regulated genes. In both cell lines, in up-regulated genes, there was a combination of pro- and anti-apoptotic genes that were significantly expressed. Gene expression results showed that more tumorigenic cells (DLD-1) went through apoptosis; however, they exhibit increased risk of resistance and recurrence, while less tumorigenic Caco-2 cells responded better to PDT, thus being suggestive of a better prognosis post-PDT treatment. In addition, the possible apoptotic mechanisms of cell death were deduced based on the genetic expression profiling of regulatory apoptotic inducing factors.

SUBMITTER: Abrahamse H

PROVIDER: S-EPMC6651415 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Genetic Aberrations Associated with Photodynamic Therapy in Colorectal Cancer Cells.

Abrahamse Heidi H Houreld Nicolette Nadene NN

International journal of molecular sciences 20190702 13

Photodynamic therapy (PDT) is a cancer treatment modality that utilizes three components: light (λ 650-750 nm), a photosensitizer (PS) and molecular oxygen, which upon activation renders the modality effective. Colorectal cancer has one of the highest incident rates as well as a high mortality rate worldwide. In this study, a zinc (Zn) metal-based phthalocyanine (ZnPcSmix) PS was used to determine its efficacy for the treatment of colon adenocarcinoma cells (DLD-1 and Caco-2). Photoactivation of ...[more]

PMID: 31269724

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Project description:Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER)-resident chaperone and a major regulator of the unfolded protein response (UPR). Accumulating evidence indicate that GRP78 is overexpressed in many cancer cell lines, and contributes to the invasion and metastasis in many human tumors. Besides, GRP78 upregulation is detected in response to different ER stress-inducing anticancer therapies, including photodynamic therapy (PDT). This study demonstrates that GRP78 mRNA and protein levels are elevated in response to PDT in various cancer cell lines. Stable overexpression of GRP78 confers resistance to PDT substantiating its cytoprotective role. Moreover, GRP78-targeting subtilase cytotoxin catalytic subunit fused with epidermal growth factor (EGF-SubA) sensitizes various cancer cells to Photofrin-mediated PDT. The combination treatment is cytotoxic to apoptosis-competent SW-900 lung cancer cells, as well as to Bax-deficient and apoptosis-resistant DU-145 prostate cancer cells. In these cells, PDT and EGF-SubA cytotoxin induce protein kinase R-like ER kinase and inositol-requiring enzyme 1 branches of UPR and also increase the level of C/EBP (CCAAT/enhancer-binding protein) homologous protein, an ER stress-associated apoptosis-promoting transcription factor. Although some apoptotic events such as disruption of mitochondrial membrane and caspase activation are detected after PDT, there is no phosphatidylserine plasma membrane externalization or DNA fragmentation, suggesting that in DU-145 cells the late apoptotic events are missing. Moreover, in SW-900 cells, EGF-SubA cytotoxin potentiates PDT-mediated cell death but attenuates PDT-induced apoptosis. In addition, the cell death cannot be reversed by caspase inhibitor z-VAD, confirming that apoptosis is not a major cell death mode triggered by the combination therapy. Moreover, no typical features of necrotic or autophagic cell death are recognized. Instead, an extensive cellular vacuolation of ER origin is observed. Altogether, these findings indicate that PDT and GRP78-targeting cytotoxin treatment can efficiently kill cancer cells independent on their apoptotic competence and triggers an atypical, non-apoptotic cell death.

Dataset Information

Genetic Aberrations Associated with Photodynamic Therapy in Colorectal Cancer Cells.

Publications

Genetic Aberrations Associated with Photodynamic Therapy in Colorectal Cancer Cells.

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