Mechanisms of cisplatin resistance in cancer cells are not fully understood. Here, we show a critical role for the ubiquitin-binding protein p62/SQSTM1 in cisplatin resistance in human ovarian cancer cells (HOCCs). Specifically, we found that cisplatin-resistant SKOV3/DDP cells express much higher levels of p62 than do cisplatin-sensitive SKOV3 cells. The protein p62 binds ubiquitinated proteins for transport to autophagic degradation, reducing apoptosis induced by endoplasmic reticulum (ER) stress in SKOV3/DDP cells. Knockdown of p62 or inhibition of autophagy using 3-methyladenine resensitises SKOV3/DDP cells to cisplatin. Collectively, our data indicate that p62 acts as a receptor or adaptor for autophagic degradation of ubiquitinated proteins, and plays an important role in preventing ER stress-induced apoptosis, leading to cisplatin resistance in HOCCs.
"These BH3-only protein analogs (or BH3 mimetics) can competitively combine with antiapoptotic proteins, including Bcl-2, Bcl-xL, Bcl-w, and Mcl-1, followed by the release of the proapoptotic proteins Bax and Bak, which ultimately induces apoptosis . An increasing number of reports in the literature have confirmed that multiple organelles and genes are involved in the mechanism of tumor chemotherapy resistance  . Two-way communication between endoplasmic reticulum (ER) and mitochondria regulates both physiological and pathological processes in cells including mitochondrial energy metabolism, lipid metabolism, Ca 2+ signaling pathways , and cell death . "
[Show abstract][Hide abstract] ABSTRACT: Tumor cells overexpress antiapoptotic proteins of the Bcl-2 (B-cell leukemia/lymphoma-2) family, which can lead to both escape from cell death and resistance to chemotherapeutic drugs. Recent studies suggest that the endoplasmic reticulum (ER) can produce proapoptotic signals, amplifying the apoptotic signaling cascade. The crosstalk between mitochondria and ER plays a decisive role in many cellular events but especially in cell death. Bcl-2 family proteins located in the ER and mitochondria can influence not only the function of the two organelles but also the interaction between them. Therefore, the Bcl-2 family of proteins may also be involved in the mechanism of tumor chemotherapy resistance by influencing crosstalk between the ER and mitochondria. In this review we will briefly discuss evidence to support this concept.
BioMed Research International 08/2014; 2014:234370. DOI:10.1155/2014/234370 · 3.17 Impact Factor
"We detected autophagy at 4 h (an earlier time point) and apoptosis at 12 h (a later time point). The autophagy-specific inhibitor 3-MA, which by itself has no toxic effects according to previous studies 20, was used to elucidate the role of autophagy in HO8910 cells that were treated with B19. As shown in Figure 5A, MTT assays indicated that 3-MA alone has no significant effects on cell viability. "
[Show abstract][Hide abstract] ABSTRACT: Background: The unfolded protein response, autophagy and endoplasmic reticulum (ER) stress-induced apoptosis regulate tumor cell fate and have become novel signaling targets for the development of cancer therapeutic drugs. Curcumin has been used to treat several different cancers, including ovarian cancer, in clinical trials and research; however, the role of ER stress and autophagy in the therapeutic effects of curcumin and new curcumin analogues remains unclear.
Methods: Cell viability was determined using the MTT assay. Apoptosis was detected using flow cytometry with PI/Annexin V-FITC staining. The expression levels of ER stress- and autophagy-related proteins were analyzed by western blotting. The activation of autophagy was detected using immunofluorescence staining.
Results: We demonstrated that B19 induced HO8910 cell apoptosis in a dose-responsive manner. We also determined and that this effect was associated with corresponding increases in a series of key components in the UPR and ER stress-mediated apoptosis pathways, followed by caspase 3 cleavage and activation. We also observed that B19 treatment induced autophagy in HO8910 cells. The inhibition of autophagy using 3-methyladenine (3-MA) increased levels of intracellular misfolded proteins, which enhanced ovarian cancer apoptosis.
Conclusions: Our data indicate that ER stress and autophagy may play a role in the apoptosis that is induced by the curcumin analogue B19 in an epithelial ovarian cancer cell line and that autophagy inhibition can increase curcumin analogue-induced apoptosis by inducing severe ER stress.
International journal of biological sciences 08/2013; 9(8):766-77. DOI:10.7150/ijbs.5711 · 4.51 Impact Factor
"These data indicate that inhibition of fusion of lysosome with Avs containing damaged components and reduced autophagic flux may be resulted from lysosomal permeability by NH 4 Cl in menadione-treated Hela cells, which enhances oxidative stress-mediated cytotoxicity through accumulation of ROS. Our previous studies found that autophagy efficiently transports cisplatin-induced misfolded proteins for degradation in cisplatin-resistant HOCCs and Hela cells, allowing cells to avoid ER stress mediated apoptosis, and thus maintaining cell homeostasis and survival (Xu et al., 2012; Yu et al., 2011). In addition, some researchers suggested that ER stress and mitochondrial dysfunction might cooperatively regulate apoptotic-signaling cascades (Lee et al., 2010; Zhao et al., 2010; Zhong et al., 2012). "
Koji Kimura, Kengo Inoue, Jun Okubo, Yumiko Ueda, Kosuke Kawaguchi, Hiroaki Sakurai, Ikuo Wada, Masashi Morita, Tsuneo Imanaka
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