Inhibition of Protein Phosphatase 1 Stimulates Noncanonical ER Stress eIF2α Activation to Enhance Fisetin-induced Chemosensitivity in HDAC Inhibitor-resistant Hepatocellular Carcinoma Cells

Abstract

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects.

CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and Apoptosis

“…ER stress triggers the UPR in carcinogenesis (Mcgrath et al, 2018;Liu J. et al, 2019;Siwecka et al, 2019). On one hand, ER stress promotes cell survival and induces drug resistance (Rzymski et al, 2009;Pandey et al, 2019;Shi et al, 2019), and on the other hand, long-term ER stress can become pro-apoptotic (Han et al, 2013;Liu Y. S. et al, 2019). UPR consists of three major signaling pathways mediated by inositol-requiring enzyme 1 (IRE-1), ATF6, and PERK.…”

Hsa-miR-107 regulates chemosensitivity and inhibits tumor growth in hepatocellular carcinoma cells

“…The whole-cell protein sample extracted by RIPA Lysis Buffer (Thermo Scientific, USA) with proteinase K and phosphatase inhibitors, as previously described [ 21 , 47 ]. Briefly, the cell pellets were lysed centrifuged at 12,000 rpm for 15 min at 4°C.…”

“…Total protein from cell samples was measured by Bradford protein assay dye (Bio-Rad, USA). According to our previous study [ 47 ], the samples (20 μg) were separated by SDS-PAGE and then transferred to polyvinylidene fluoride membranes (Millipore, Belford, Massachusetts, USA) by the Bio-Rad western blotting system. Briefly, the membranes were blocked for 1 hr with blocking buffer then incubated with specific primary antibodies (dilution 1:1000) at 4°C overnight.…”

Fabrication of Supercritical Antisolvent (SAS) Process-Assisted Fisetin-Encapsulated Poly (Vinyl Pyrrolidone) (PVP) Nanocomposites for Improved Anticancer Therapy

“…Fisetin (FIS, C 15 H 10 O 6 ), a widely spread flavonoid in many fruits and vegetables [1,2], has garnered enormous interest due to its numerous biological activities, including its antioxidant [3], antibacterial [4,5], anticancer, and neuroprotective effects [6], among other therapeutic properties. Specifically, in terms of antiproliferative effects, FIS is a highly active flavonoid against multiple types of cancers in various organs such as the colon, breasts, lungs, and liver [7][8][9][10][11][12]. As the most common and Nanomaterials 2020, 10, 322 2 of 14 deadly cancer in women, breast cancer results in the deaths of numerous women worldwide.…”