Downregulation of high mobility group protein box‑1 resensitizes ovarian cancer cells to carboplatin

Abstract

Ovarian cancer, one of the most common types of cancer, has the highest mortality among all gynecological malignancies. The development of acquired drug resistance is the leading cause of chemotherapy failure. To study the mechanism underlying drug resistance in ovarian cancer, a drug-resistant ovarian cancer SKOV3 cell line was developed using the chemotherapeutic agent carboplatin (SKOV3-Carb) in the present study. It has been reported that high-mobility group protein box-1 (HMGB1) is associated with the chemoresistance of tumor cells. Therefore, the probable involvement of HMGB1 in the development of carboplatin resistance in ovarian cancer SKOV3 cells was investigated. HMGB1 has been reported to be overexpressed in carboplatin-resistant SKOV3-Carb cells compared with control SKOV3 cells. Subsequently, the expression of HMGB1 was silenced by small interference RNA technology. Reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that mRNA and protein expression levels of HMGB1 were significantly inhibited in HMGB1-silenced cells. Cell proliferation and apoptosis analyses were performed to evaluate the effect of HMGB1 silencing on resistant ovarian cancer cells. An MTT assay revealed that the proliferation of HMGB1-silenced SKOV3 and SKOV3-Carb cells were decreased compared with the proliferation of non-silenced control cells. Additionally, HMGB1 protein expression levels in SKOV3 cells, but not in SKOV3-Carb cells, were decreased in response to carboplatin treatment. Annexin V-fluorescein isothiocyanate/propidium iodide staining demonstrated that HMGB1 silencing enhanced the effects of carboplatin in inducing the apoptosis of SKOV3-Carb cells relative to HMGB1 non-silenced control cells. The results of the present study suggested that HMGB1 may be involved in the development of carboplatin resistance in ovarian cancer SKOV3 cells and that HMGB1 silencing may induce the sensitization of carboplatin-resistant ovarian cancer cells to carboplatin. Therefore, HMGB1 may be considered as a potent therapeutic target for increasing the sensitivity of ovarian cancer cells to carboplatin in order to improve the treatment and prognosis of ovarian cancer.

The HMGB1-2 Ovarian Cancer Interactome. The Role of HMGB Proteins and Their Interacting Partners MIEN1 and NOP53 in Ovary Cancer and Drug-Response

“…Accordingly, HMGB1 or HMGB2 silencing decrease cell-viability of SKOV-3 cells exposed to carboplatin ( Figure 6 ). Our data support the role of HMGB1 in resistance to carboplatin that was previously reported [ 15 ]. No data were previously available about the role of HMGB1 or HMGB2 in the resistance to paclitaxel, olaparib or bevacizumab in EOC treatment, although HMGB1 had been reported as a possible prognosis biomarker of bevacizumab treatment in non-small-cell lung cancer [ 130 ] and bevacizumab and HMGB1 have been related to malignant mesothelioma [ 131 ].…”

“…SKOV-3 and IOSE-80 cells at 80% confluence were exposed during 48 h to different treatments, using drug concentrations and conditions selected according to previous studies. Paclitaxel was used at 25 μM [ 133 ]; carboplatin at 25 μg/mL [ 15 ]; olaparib to 2 μM [ 134 ]; and bevacizumab at 100 µg/mL [ 135 ] Paclitaxel was purchased to Sigma Aldrich Inc. (St. Louis, MO, USA) and olaparib, bevacizumab and carboplatin were provided by the Pharmacy Service of the Teresa Herrera hospital (INIBIC). In parallel, cells were grown with the same amount of vehicle-buffer used to prepare drug solutions, or with an unspecific IgG not directed to vascular endothelial growth factor as control of bevacizumab treatment.…”

“…HMGB1 and HMGB2 proteins have been also related to chemotherapy resistance in serous EOC [ 13 ]. High expression of HMGB1 has been related to cisplatin resistance [ 14 ] and downregulation of HMGB1 re-sensitizes ovarian cancer cells to carboplatin [ 15 ]. HMGB2 expression has been associated to resistance against oxaliplatin and cisplatin [ 16 ].…”

HMGB1 protein as a novel target for cancer

“…Expression of HMGB1 protein was found over-expressed in ovarian cancer but the expression was linked with poor clinico-pathologic explanation [ 86 ]. Like many other cancer HMGB1 up-regulated expression was correlated with genesis, growth and metastasis of ovarian cancer [ 87 ]. The gene knockout strategy for HMGB1 was found to suppress cell proliferation by cell-cycle arrest at G1/G0 phase and decreased expression of cyclin-D1 and PCNA [ 86 ].…”

Mode of action of carboplatin via activating p53/miR‐145 axis in head and neck cancers

“…44 These cross-links inhibit DNA replication and repair, leading to transcription errors and inhibition of cellular functions. 44,45 It promotes cell cycle arrest, inhibits proliferation, and induces apoptosis of cancer cells through activation of the p53 signaling pathway. 46,47 Carboplatin is characterized by formation of DNA lesions and thereby activation of the p53 signaling pathway.…”