Dataset Information

KRAS K104 modification affects the KRAS^G12D-GEF interaction and mediates cell growth and motility.

ABSTRACT: Mutant RAS genes play an important role in regulating tumors through lysine residue 104 to impair GEF-induced nucleotide exchange, but the regulatory role of KRAS K104 modification on the KRAS^G12D mutant remains unclear. Therefore, we simulated the acetylation site on the KRAS^G12D three-dimensional protein structure, including KRAS^G12D, KRAS^G12D/K104A and KRAS^G12D/K104Q, and determined their trajectories and binding free energy with GEF. KRAS^G12D/K104Q induced structural changes in the ?2- and ?3-helices, promoted KRAS instability and hampered GEF binding (??G?=?6.14 kJ/mol). We found decreased binding to the Raf1 RBD by KRAS^G12D/K104Q and reduced cell growth, invasion and migration. Based on whole-genome cDNA microarray analysis, KRAS^G12D/K104Q decreased expression of NPIPA2, DUSP1 and IL6 in lung and ovarian cancer cells. This study reports computational and experimental analyses of Lys104 of KRAS^G12D and GEF, and the findings provide a target for exploration for future treatment.

SUBMITTER: Chen CC

PROVIDER: S-EPMC7567070 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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KRAS K104 modification affects the KRASG12D-GEF interaction and mediates cell growth and motility.

Chen Chih-Chieh CC Hsu Chia-Yi CY Lin Hsiao-Yun HY Zeng Hong-Qi HQ Cheng Kuang-Hung KH Wu Chia-Wei CW Tsai Eing-Mei EM Hsieh Tsung-Hua TH

Scientific reports 20201015 1

Mutant RAS genes play an important role in regulating tumors through lysine residue 104 to impair GEF-induced nucleotide exchange, but the regulatory role of KRAS K104 modification on the KRASG12D mutant remains unclear. Therefore, we simulated the acetylation site on the KRASG12D three-dimensional protein structure, including KRASG12D, KRASG12D/K104A and KRASG12D/K104Q, and determined their trajectories and binding free energy with GEF. KRA ...[more]

PMID: 33060649

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Project description:Pancreatic cancer (PC) has a very low survival rate mainly due to late diagnosis and refractoriness to therapies. The latter also cause adverse effects negatively affecting the patients' quality of life, often requiring dose reduction or discontinuation of scheduled treatments, compromising the chances of cure. We explored the effects of a specific probiotic blend on PC mice xenografted with KRAS wild-type or KRASG12D mutated cell lines alone or together with gemcitabine+nab-paclitaxel treatment to then assess tumor volume and clinical pathological variables. Beside a semi-quantitative histopathological evaluation of murine tumor and large intestine samples, histochemical and immunohistochemical analyses were carried out to evaluate collagen deposition, proliferation index Ki67, immunological microenvironment tumor-associated, DNA damage markers and also mucin production. Blood cellular and biochemical parameters and serum metabolomics were further analyzed. 16S sequencing was performed to analyze the composition of fecal microbiota. Gemcitabine+nab-paclitaxel treatment impaired gut microbial profile in KRAS wild-type and KRASG12D mice. Counteracting gemcitabine+nab-paclitaxel- induced dysbiosis through the administration of probiotics ameliorated chemotherapy side effects and decreased cancer-associated stromatogenesis. Milder intestinal damage and improved blood count were also observed upon probiotics treatment as well as a positive effect on fecal microbiota, yielding an increase in species richness and in short chain fatty acids producing- bacteria. Mice' serum metabolomic profiles revealed significant drops in many amino acids upon probiotics administration in KRAS wild-type mice while in animals transplanted with PANC-1 KRASG12D mutated all treated groups showed a sharp decline in serum levels of bile acids with respect to control mice. These results suggest that counteracting gemcitabine+nab-paclitaxel-induced dysbiosis ameliorates chemotherapy side effects by restoring a favorable microbiota composition. Relieving adverse effects of the chemotherapy through microbiota manipulation could be a desirable strategy in order to improve pancreatic cancer patients' quality of life and to increase the chance of cure.

Dataset Information

KRAS K104 modification affects the KRAS^G12D-GEF interaction and mediates cell growth and motility.

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KRAS K104 modification affects the KRAS<sup>G12D</sup>-GEF interaction and mediates cell growth and motility.

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