TY - JOUR

T1 - Mycoplasma hyorhinis reduces sensitivity of human lung carcinoma cells to Nutlin-3 and promotes their malignant phenotype

AU - Boyarskikh, Uljana A.

AU - Shadrina, Alexandra S.

AU - Smetanina, Mariya A.

AU - Tsepilov, Yakov A.

AU - Oscorbin, Igor P.

AU - Kozlov, Vadim V.

AU - Kel, Alexander E.

AU - Filipenko, Maxim L.

N1 - Publisher Copyright: © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Purpose: MDM2 inhibitors are promising anticancer agents that induce cell cycle arrest and tumor cells death via p53 reactivation. We examined the influence of Mycoplasma hyorhinis infection on sensitivity of human lung carcinoma cells NCI-H292 to MDM2 inhibitor Nutlin-3. In order to unveil possible mechanisms underlying the revealed effect, we investigated gene expression changes and signal transduction networks activated in NCI-H292 cells in response to mycoplasma infection. Methods: Sensitivity of NCI-Н292 cells to Nutlin-3 was estimated by resazurin-based cell viability assay. Genome-wide transcriptional profiles of NCI-H292 and NCI-Н292Myc.h cell lines were determined using Illumina Human HT-12 v3 Expression BeadChip. Search for key transcription factors and key node molecules was performed using the geneXplain platform. Ability for anchorage-independent growth was tested by soft agar colony formation assay. Results: NCI-Н292Myc.h cells were shown to be 1.5- and 5.2-fold more resistant to killing by Nutlin-3 at concentrations of 15 and 30 µM than uninfected NCI-Н292 cells (P < 0.05 and P < 0.001, respectively). Transcriptome analysis revealed differential expression of multiple genes involved in cancer progression and metastasis as well as epithelial–mesenchymal transition (EMT). Moreover, we have shown experimentally that NCI-Н292Myc.h cells were more capable of growing and dividing without binding to a substrate. The most likely mechanism explaining the observed changes was found to be TLR4- and IL-1b-mediated activation of NF-κB pathway. Conclusions: Our results provide evidence that mycoplasma infection is an important factor modulating the effect of MDM2 inhibitors on cancer cells and is able to induce EMT-related changes.

AB - Purpose: MDM2 inhibitors are promising anticancer agents that induce cell cycle arrest and tumor cells death via p53 reactivation. We examined the influence of Mycoplasma hyorhinis infection on sensitivity of human lung carcinoma cells NCI-H292 to MDM2 inhibitor Nutlin-3. In order to unveil possible mechanisms underlying the revealed effect, we investigated gene expression changes and signal transduction networks activated in NCI-H292 cells in response to mycoplasma infection. Methods: Sensitivity of NCI-Н292 cells to Nutlin-3 was estimated by resazurin-based cell viability assay. Genome-wide transcriptional profiles of NCI-H292 and NCI-Н292Myc.h cell lines were determined using Illumina Human HT-12 v3 Expression BeadChip. Search for key transcription factors and key node molecules was performed using the geneXplain platform. Ability for anchorage-independent growth was tested by soft agar colony formation assay. Results: NCI-Н292Myc.h cells were shown to be 1.5- and 5.2-fold more resistant to killing by Nutlin-3 at concentrations of 15 and 30 µM than uninfected NCI-Н292 cells (P < 0.05 and P < 0.001, respectively). Transcriptome analysis revealed differential expression of multiple genes involved in cancer progression and metastasis as well as epithelial–mesenchymal transition (EMT). Moreover, we have shown experimentally that NCI-Н292Myc.h cells were more capable of growing and dividing without binding to a substrate. The most likely mechanism explaining the observed changes was found to be TLR4- and IL-1b-mediated activation of NF-κB pathway. Conclusions: Our results provide evidence that mycoplasma infection is an important factor modulating the effect of MDM2 inhibitors on cancer cells and is able to induce EMT-related changes.

KW - Epithelial–mesenchymal transition

KW - Lung cancer

KW - MDM2 inhibitor

KW - Mycoplasma

KW - NF-κB

KW - Nutlin-3

KW - SIGNALING PATHWAYS

KW - ACTIVATION

KW - METASTASIS

KW - CANCER CELLS

KW - EPITHELIAL-MESENCHYMAL TRANSITION

KW - Epithelial-mesenchymal transition

KW - NF-kappa B

KW - GASTRIC-CANCER

KW - COLORECTAL-CANCER

KW - INFECTION

KW - NF-KAPPA-B

KW - POTENTIAL ROLE

KW - Humans

KW - Middle Aged

KW - Transcriptome

KW - Drug Resistance, Neoplasm

KW - Male

KW - Young Adult

KW - Imidazoles/pharmacology

KW - Lung Neoplasms/drug therapy

KW - Aged, 80 and over

KW - Adult

KW - Female

KW - Mycoplasma Infections/metabolism

KW - Gene Expression/drug effects

KW - Mycoplasma hyorhinis/physiology

KW - Signal Transduction

KW - Piperazines/pharmacology

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Cell Line, Tumor

KW - Aged

KW - Carcinoma, Mucoepidermoid/drug therapy

UR - http://www.scopus.com/inward/record.url?scp=85046692454&partnerID=8YFLogxK

U2 - 10.1007/s00432-018-2658-9

DO - 10.1007/s00432-018-2658-9

M3 - Article

C2 - 29737431

AN - SCOPUS:85046692454

VL - 144

SP - 1289

EP - 1300

JO - Journal of Cancer Research and Clinical Oncology

JF - Journal of Cancer Research and Clinical Oncology

SN - 0171-5216

IS - 7

ER -