Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

Abstract

TP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the TP53 gene. In the present study, we characterized colon cancer cells (HCT116 p53 −/−) with TP53 deletion, a sub-line derived from HCT116-p53 +/+ cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 p53 −/− cells: RND3/RhoE (235.6-fold up-regulated), DCLK1 (60.2-fold up-regulated), LBH (31.9-fold up-regulated), MYB (28.9-fold up-regulated), TACSTD2 (110.1-fold down-regulated), NRIP1 (81.5-fold down-regulated) and HLA-DMB (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to TP53 deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-p53 −/− cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-p53 +/+ cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This may have important implications for future treatment strategies.

Novel cationic cryptides in Penaeus vannamei demonstrate antimicrobial and anti-cancer activities

“…All the selected cryptides demonstrated anti-cancer effects against most of the tested cancer cell lines. The observed resistance of HCT 116 cells to the tested cryptides could be attributed to several factors, including high membrane rigidity due to higher cholesterol levels 44 and genomic aberrations that may contribute to drug resistance 45 . The resistance of the SH-SY5Y cells towards four of the five peptides tested may also be due to its relatively higher mitochondrial membrane potential and electrical membrane activity, inhibiting the attraction between the cationic cryptides and cellular and mitochondrial membranes 46 .…”

Emerging role of MYB transcription factors in cancer drug resistance

“…Transcription via p300-CREB enhanced oxaliplatin resistance in CRC by upregulation of the ABC transporter multidrug resistance-associated protein 2 (MRP2), while p300-MYB was more involved in gastrointestinal differentiation [52] . The role of MYBL2 in oxaliplatin resistance of CRC cells was studied and MYBL2 was shown to induce the expression of the lncRNA CCAT1, which led to upregulation of suppressor of cytokine signaling 3 (SOCS3) and resistance to oxaliplatin in vitro and in vivo [53] . Resistance of CRCs to cisplatin and oxaliplatin was also associated with p53 absence in p53-knockout CRC cells.…”

Progress in Anticancer Drug Development Targeting Ubiquitination-Related Factors

“…p53 dysfunction is closely related to human cancers and neurodegenerative diseases [ 65 , 66 ]. Deletion in the p53 gene aggravates deterioration of cancers [ 67 , 68 , 69 , 70 ]. RING-type E3 MDM2 binds to p53 through its N terminus to ubiquitinate p53 protein [ 71 , 72 , 73 ].…”