Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

Abstract

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner

“…In this study, we compared two p53 mutant HNSCC cell lines, OECM1 and Detroit 562 cells, with different p53 mutations, and treated them with p73 activator(s). The Detroit 562 cell line has a p53 R175H mutation [17], and OECM-1 has a p53 V173L mutation [18]. We found that both RETRA and NSC59984 had a better cytotoxic response in OECM1 cells than in Detroit 562 cells.…”

“…In this study, we found that two p73 activators, RETRA and NSC59984, have much higher cytotoxicity in OECM1 cells than in Detroit 562 cells (Figure 1). Detroit 562 cells have a p53 R175H mutation [17], and OECM-1 cells have a p53 V173L mutation [18]. The p73 specific downstream genes NEU4, JAG2, LIG1 and G6PD [21][22][23][24] were upregulated within RETRA-or NSC59984-treated OECM1 cells (Figure 2).…”

Identification of plasma hsa_circ_0000190 and 0001649 as biomarkers for predicting the recurrence and treatment response of patients with oral squamous cell carcinoma

“…The parental and cisplatin-resistant OECM1 cancer cell lines were grown in Roswell Park Memorial Institute Medium (RPMI; #11-100; Biological Industries, Beit Haemek, Israel) supplemented with 10% Fetal Bovine Serum (FBS; #10438-028; Thermo Fisher Scientific, Waltham, MA, USA), 1% penicillin-streptomycin (#15140-122; Thermo Fisher Scientific), and 1% glutamine. The characteristics of these cells were described in the previous study 18 Subculturing was performed using trypsin-EDTA. The medium was refreshed every 2 days.…”

The Molecular Basis and Therapeutic Aspects of Cisplatin Resistance in Oral Squamous Cell Carcinoma

“…Interestingly, this study also found that p53 nuclear translocation occurred in endoplasmic reticulum stress-adapted cells and that intracellular cisplatin uptake was not significantly different from control cells, but the accumulation of cisplatininduced DNA damage was dramatically reduced. Once p53 was knocked down, the cells could hardly tolerate prolonged ER stress and cisplatin treatment (25). This suggested that prolonged ER stress might counteract the effects of cisplatin by repairing DNA damage through the Polh-dependent TLS pathway, and inducing p53 nuclear translocation to make cells tolerate DNA damage.…”