Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance

In the present study, cisplatin, artemisinin, and oleanolic acid were evaluated alone, and in combination, on human ovarian A2780, A2780ZD0473R, and A2780cisR cancer cell lines, with the aim of overcoming cisplatin resistance and side effects. Cytotoxicity was assessed by MTT reduction assay. Combination index (CI) values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. Moreover, 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism, and biosynthetic processes and drug resistance and detoxification. Results indicate that appropriately sequenced combinations of cisplatin with artemisinin (ART) and oleanolic acid (OA) may provide a means to reduce side effects and circumvent platinum resistance.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models

Althurwi

Beale

et al. 2020

IJMS

“…P4HB is proved to be upregulated in a variety of cancers, such as lung cancer [10], diffuse glioma [9], colon cancer [11]. As a result, P4HB has been reported by numerous researches to be a potential target for cancer therapy [12][13][14]. But studies referred to GC were rather limited.…”

Section: Introductionmentioning

confidence: 99%

Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastric Cancer

Zhao

et al. 2020

Preprint

Background: Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) are represent for poor prognosis of various cancers. However, rare research investigate the correlation of them in cancer. This study aimed to investigate the correlation and prognostic value of P4HB and GRP78 expression along with clinical features in gastric cancer (GC).Methods: A total of 150 GC tissue samples separately evaluated P4HB and GRP78 protein expression by immunohistochemistry. Association of P4HB and GRP78 expression with clinicopathological features was analyzed. Bioinformatics analyses were performed to find correlation between mRNAs and pathways. Kaplan-Meier analyses were taken to compare survival curves. Univariate and multivariate Cox regression models used to analyze the impact of prognostic factors on overall survival (OS). A prognostic nomogram was constructed based on the multivariate Cox regression model, and compared to TNM stage in discrimination ability and clinical usefulness.Results: P4HB and GRP78 expression were both associated with tumor invasion and lymph node metastasis. P4HB protein positively correlated with GRP78, as well as the same tendency of mRNAs in both GC tissue and cell databases. Bioinformatics analyses indicated that P4HB and GRP78 may be associated with protein folding and response to ER stress, and the protein processing in ER pathway. High single or co-expression of P4HB and GRP78 represented for a shorter OS. When stratified by postoperative adjuvant chemotherapy, the high co-expression was only related to unfavorable prognosis of with chemotherapy group, especially in advanced stage. Multivariate Cox regression analysis identified co-expression of P4HB and GRP78 as an independent prognostic factor for OS. The nomogram including the co-expression was better than TNM stage in discrimination ability and clinical usefulness through the receiver operating characteristic (ROC) and decision curve analysis (DCA) curves.Conclusion: P4HB was positively correlated with GRP78 expression, co-expression of them was an independent prognostic factor, could serve as a predictive marker for GC patients with postoperative adjuvant chemotherapy in advanced stage.

“…P4HB is proved to be upregulated in a variety of cancers, such as diffuse glioma [9], lung cancer [10], and colon cancer [11]. As a result, P4HB has been reported by numerous researches to be a potential target for cancer therapy [12][13][14]. But studies involved GC were rather limited.…”

Section: Introductionmentioning

confidence: 99%

Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastric Cancer

Zhao

et al. 2020

Preprint

Background: Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore the correlation and prognostic value of P4HB and GRP78 expression combined with clinical features in gastric cancer (GC).Methods: 150 GC tissue samples evaluated P4HB and GRP78 protein expression by immunohistochemistry separately. Association of the expression with clinicopathological features was analyzed. To explore correlation between their mRNAs and pathways, bioinformatics analyses were performed. Kaplan-Meier analyses were taken to compare survival curves. Univariate and multivariate Cox regression models were used to analyze potential prognostic factors of overall survival (OS). Basing on the multivariate Cox regression model, a prognostic nomogram was constructed, discrimination ability and clinical usefulness of which were compared to TNM stageResults: P4HB and GRP78 expression were both associated with tumor invasion and lymph node metastasis. P4HB protein positive correlated with GRP78, as the same tendency of mRNAs in both GC tissue and cell databases. Bioinformatics analyses indicated that P4HB and GRP78 may be associated with protein folding and response to ER stress, as well as with the protein processing in ER pathway. High single expression or co-expression of P4HB and GRP78 indicated a shorter OS. When stratified by postoperative adjuvant chemotherapy, high co-expression was only represented for unfavorable prognosis in the group with chemotherapy, especially in advanced stage. Multivariate Cox regression analysis identified differentiation (P = 0.020, HR = 1.846, 95% CI: 1.099-3.101), TNM stage (P < 0.001, HR = 3.124, 95% CI: 1.870-5.217), postoperative adjuvant chemotherapy (P = 0.005, HR = 0.507, 95% CI: 0.317-0.810) and P4HB and GRP78 co-expression (P = 0.002, HR = 2.304, 95% CI: 1.355-3.915) were independent prognostic factors for OS. The nomogram was better than TNM stage in discrimination ability and clinical usefulness from the receiver operating characteristic (ROC) and decision curve analysis (DCA) curves.Conclusion: P4HB may positive correlate with GRP78 expression in GC. Co-expression of them can be an independent prognostic factor, serving as a predictive biomarker for GC patients, especially for advanced stage with postoperative adjuvant chemotherapy. And the nomogram may be better than TNM stage in discrimination ability and clinical usefulness.