Endoplasmic reticulum stress and IRE-1 signaling cause apoptosis in colon cancer cells in response to andrographolide treatment

Abstract

The plant metabolite andrographolide induces cell cycle arrest and apoptosis in cancer cells. The mechanism(s) by which andrographolide induces apoptosis however, have not been elucidated. The present study was performed to determine the molecular events that promote apoptosis in andrographolide treated cells using T84, HCT116 and COLO 205 colon cancer cell lines. Andrographolide was determined to limit colony formation and Ki67 expression, alter nuclear morphology, increase cytoplasmic histone-associated-DNA-fragments, and increase cleaved caspase-3 levels. Andrographolide also induced significantly higher expression of endoplasmic reticulum (ER) stress proteins GRP-78 and IRE-1 by 48 h but not PERK or ATF6. Apoptosis signaling molecules BAX, spliced XBP-1 and CHOP were also significantly increased. Moreover, chemical inhibition of ER stress or IRE-1 depletion with siRNA in andrographolide treated cells significantly limited expression of IRE-1 and CHOP as determined by immunofluorescence staining, real time PCR, or immunobloting. This was accompanied by a decreased BAX/Bcl-2 ratio. Andrographolide significantly promotes cancer cell death compared to normal cells. These data demonstrate that andrographolide associated ER stress contributes to apoptosis through the activation of a pro-apoptotic GRP-78/IRE-1/XBP-1/CHOP signaling pathway.

Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

“…It has been demonstrated that three ER stress signals are differentially activated under different stimulation. For example, a plant metabolite andrographolide activates IRE1a but not PERK and ATF6 in cancer cells [Banerjee, Ahmed, Yang, Czinn, & Blanchard, 2016]. However, bortezomib, an selective inhibitor of the 26S proteasome, induces the activation of PERK and ATF6 but not IRE1a in myeloma cells [Davenport et al, 2007].…”

MiR-410 Acts as a Tumor Suppressor in Estrogen Receptor-Positive Breast Cancer Cells by Directly Targeting ERLIN2 via the ERS Pathway

“…For example, extracts of Annona muricata can cause apoptosis of cancer cells and inhibit tumor growth through the activation of ERS pathway, with the upregulation of GRP94, HSP70, Bip and CHOP, as well as the upregulated phosphorylation of PERK and eIF2α [32]. Andrographolide induces apoptosis of colon cancer cells via the upregulation of ERS proteins GRP78, CHOP as well as the decreased BAX/Bcl-2 ration [33]. ERS pathway is also reported to participate in the malignancy of diverse cancers, such as the metastasis of breast cancer [34,35], the poor progression of gastric carcinoma [36] as well as anti-cancer drug resistance of lung cancer cells and ovarian carcinoma cells [37].…”

Chemical evaluation and cytotoxic mechanism investigation of Clinacanthus nutans extract in lymphoma SUP‐T1 cells

“…In addition, protein production is affected in damage, and then unfolded protein response (UPR) takes place where PERK, CHOP, and GRP78 are generated. UPR triggers ER stress and ER stress‐dependent apoptosis . In conclusion, we will demonstrate that multiple cell death mechanisms of Clinacanthus nutans involved in lymphoma and leukemia cells show anti‐lymphoma potential in cancer alternative therapy.…”

“…UPR triggers ER stress and ER stress-dependent apoptosis. 18 In conclusion, we will demonstrate that multiple cell death mechanisms of Clinacanthus nutans involved in lymphoma and leukemia cells show anti-lymphoma potential in cancer alternative therapy.…”