RESUMEN
The mechanism of cisplatin resistance in ovarian cancer is not fully understood. In the present study, we showed a critical role for endoplasmic reticulum (ER) stress tolerance in mediating cisplatin resistance in human ovarian cancer cells. We found cisplatin to inhibit the proliferation of two ovarian cancer cell lines: cisplatin-sensitive SKOV3 cells and cisplatinresistant SKOV3/DDP cells. However, the effect was greater in the cisplatin-sensitive SKOV3 cells. Cisplatin treatment induced ER stress in the SKOV3 cells but not in the SKOV3/DDP cells. Cisplatin-induced Ca2+ flow from the ER into mitochondria caused mitochondrial calcium overload, which amplified proapoptotic signaling in the cisplatin-sensitive SKOV3 cells. ER stress-mediated apoptosis and mitochondrial pathway-dependent apoptosis were induced in the cisplatin-sensitive SKOV3 cells, but not in the cisplatin-resistant SKOV3/DDP cells. Moreover, there were more ER-mitochondria contacts in the cisplatin-treated SKOV3 cells. Collectively, our data indicated that tolerance to cisplatin-induced ER stress inhibits ER stress-mediated apoptosis, prevents an imbalance in ER and mitochondrial calcium homeostasis and maintains cell survival, thus leading to cisplatin resistance in ovarian cancer cells.
Asunto(s)
Cisplatino/administración & dosificación , Resistencia a Antineoplásicos/genética , Estrés del Retículo Endoplásmico/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/genética , Femenino , Homeostasis , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patologíaRESUMEN
Cisplatin is a commonly used chemotherapeutic agent; however, the development of acquired resistance limits its application. Here, we demonstrate that 2-deoxy-d-glucose (2-DG) enhanced the antitumor effects of cisplatin in SKOV3 cells, which include inhibition of proliferation and promotion of apoptosis. Additionally, either cisplatin or 2-DG alone could upregulate the endoplasmic reticulum (ER) stress-associated protein glucose-regulated protein-78 (GRP78). Moreover, exposure to 2-DG increased the expression of GRP78 induced by cisplatin. Cisplatin also upregulated ER stress-associated apoptotic protein 153/C/EBP homology protein (CHOP) in SKOV3 cells. While treatment with 2-DG alone could not upregulate the CHOP expression, a combination of both 2-DG and cisplatin increased the protein levels of CHOP above those induced by Cisplatin alone. Finally, cisplatin mediated an increase in ATP stores within acidic vesicles, whereas 2-DG decreased this effect. These data demonstrate that 2-DG sensitizes SKOV3 cells to cisplatin by increasing ER stress and decreasing ATP stores in acidic vesicles.
Asunto(s)
Adenosina Trifosfato/metabolismo , Antineoplásicos/farmacología , Cisplatino/farmacología , Desoxiglucosa/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Neoplasias Ováricas/patología , Ácidos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Cisplatin is commonly used as a therapeutic agent, despite its known adverse side effects and the occurrence of drug resistance. The development of novel methods for combination therapy with cisplatin is required in order to circumvent these limitations of cisplatin alone. The proteasome inhibitor lactacystin (LAC) has been indicated to produce anti-tumor effects, and has previously been used as an antitumor agent in cancer treatment research; however, its effects in combination with cisplatin treatment are unknown. In the current study, the effects of LAC in combination with cisplatin treatment were investigated in HeLa human cervical cancer (HCC) cells. The results demonstrated that cisplatin treatment inhibited cell growth and induced cell apoptosis. HeLa cell exposure to cisplatin induced endoplasmic reticulum (ER) stress-associated apoptosis, and LAC treatment increased levels of cell apoptosis and the activation of caspase-3. Specifically, LAC treatment increased the cisplatin-induced expression of PDI, GRP78, CHOP, cleaved caspase-4 and cleaved caspase-3. Together, these data indicate that LAC is able to enhance cisplatin cytotoxicity by increasing ER stress-associated apoptosis in HeLa cells.