XPA, XPC, and XPD Modulate Sensitivity in Gastric Cisplatin Resistance Cancer Cells

Abstract

Cisplatin is an election drug widely used in clinic for the treatment of advanced gastric cancer. However, the heterogeneity of the gastric tumors and its resistance to the drugs, make in some cases the response very low and the prognosis unpredictable. In this manuscript we aim to find the molecular processes involved in cisplatin-induced apoptosis in two gastric cancer cell lines with different sensitivity to the treatment: AGS and MKN45. The apoptosis induction is higher in MKN45 than in AGS cells in response to CDDP. The intrinsic apoptotic pathway study revealed that MKN45 cells undergo degradation of Mcl-1 together with an increase of Bid and Bad levels, which results in sensitivity to CDDP. In addition, DNA repair NER pathway is impair in MKN45 cells due to low levels of XPC and the absence of translocation of XPA and XPD to the nucleus after stimuli. Altogether, these results suggest that NER and Bcl-2 protein family proteins are potential targets to improve the response to cisplatin treatment.

New Findings in the Signaling Pathways of cis and trans Platinum Iodido Complexes’ Interaction with DNA of Cancer Cells

“…Finally, the antiapoptotic Mcl1 expression analysis after 6 h of treatment shows that CDDP produces clear degradation as it is described in the literature after 48 h. 7 Compound 1 shows the same profile. No degradation is observed neither with 2 nor with 4 , but a surprisingly marked degradation is observed with 3 h treatment.…”

A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma

“…ERCC2 encodes XPD, a protein associated with regulation of TFIIH-mediated transcription and DNA damage. XPD has effects on progression of a broad palette of tumor types when mutated or altered—increased or decreased—in expression, and variants in ERCC2 have been associated with altered drug response, especially platinum-based therapies ( Du et al., 2014 ; Fu et al., 2017 ; Tan et al., 2017 ; Pajuelo-Lozano et al., 2018 ; Liu et al., 2019 ). This may have contributed to the patient's failure to respond to earlier carboplatin-based therapy.…”

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

“…Binding of XPC to DNA is necessary for the recruitment of TFIIH, making it the rate-limiting step of GG-NER [ 58 ]. Studies have shown that enhanced expression of XPC increases resistance in many types of cancer [ 59 , 60 , 61 ]. Additionally, studies involving many different cancer cell lines have shown that the overexpression of XPC leads to cisplatin resistance ( Figure 2 ) while knockout of the gene enhances sensitivity.…”