The systemic tumor response to RNase A treatment affects the expression of genes involved in maintaining cell malignancy

Abstract

Recently, pancreatic RNase A was shown to inhibit tumor and metastasis growth that accompanied by global alteration of miRNA profiles in the blood and tumor tissue (Mironova et al., 2013). Here, we performed a whole transcriptome analysis of murine Lewis lung carcinoma (LLC) after treatment of tumor-bearing mice with RNase A. We identified 966 differentially expressed transcripts in LLC tumors, of which 322 were upregulated and 644 were downregulated after RNase A treatment. Many of these genes are involved in signaling pathways that regulate energy metabolism, cell-growth promoting and transforming activity, modulation of the cancer microenvironment and extracellular matrix components, and cellular proliferation and differentiation. Following RNase A treatment, we detected an upregulation of carbohydrate metabolism, inositol phosphate cascade and oxidative phosphorylation, re-arrangement of cell adhesion, cell cycle control, apoptosis, and transcription. Whereas cancer-related signaling pathways (e.g., TGF-beta, JAK/STAT, and Wnt) were downregulated following RNase A treatment, as in the case of the PI3K/AKT pathway, which is involved in the progression of non-small lung cancer. RNase A therapy resulted in the downregulation of genes that inhibit the biogenesis of some miRNAs, particularly the let-7 miRNA family.Taken together, our data suggest that the antitumor activity and decreased invasion potential of tumor cells caused by RNase A are associated with enhanced energy cascade functioning, rearrangement of cancer-related events regulating cell growth and dissemination, and attenuation of signaling pathways having tumor-promoting activity. Thus, RNase A can be proposed as a potential component of anticancer therapy with multiple modes of action.

RNase A Promotes Proliferation of Neuronal Progenitor Cells via an ERK-Dependent Pathway

“…Rana catesbeiana RNase A induces cell death of human glioblastoma cell lines (Chen et al, 2015 ). Intramuscular injection of RNase A suppresses growth and metastasis of transplanted murine Lewis lung carcinoma in mice (Mironova et al, 2013 , 2017 ). Use of mutated human RNases as anti-tumor drugs has been suggested (Suzuki et al, 1999 ; Attery et al, 2018 ).…”

“…They share similar primary sequences and a common disulfide-bonded tertiary conformation (Beintema, 1998 ). Though sequences are similar, the mammalian RNase A superfamily is one of the most rapidly-evolving gene families in mammals (Cho et al, 2005 ), which may be relevant to the versatile functions of this family, including anti-bacterial and anti-viral activities (Rosenberg, 2008 ; Gupta et al, 2013 ; Rademacher et al, 2016 ), inhibition or promotion of tumor growth and metastasis (Suzuki et al, 1999 ; Mironova et al, 2013 , 2017 ; Chen et al, 2015 ; Attery et al, 2018 ; Wang et al, 2018 ), angiogenesis (Folkman and Klagsbrun, 1987 ; Gao and Xu, 2008 ; Sheng and Xu, 2016 ; Lyons et al, 2017 ), and cell proliferation (Li et al, 2013 ; Yu et al, 2017 ; Wang et al, 2018 ).…”

PEGylated gold nanoparticles-ribonuclease induced oxidative stress and apoptosis in colorectal cancer cells

“…21 RNases represent a new class of cytotoxic and non-mutagenic enzymes, that can inhibit the proliferation of cancer cells through the catalytic cleavage of phosphodiester bonds in various types of single-stranded RNA (e.g., tRNA, rRNA, mRNA, and non-coding RNA), and hence, influence several signaling pathways, as well as protein biosynthesis at transcription and translation stages. 22,23 However, the presence of cytosolic ribonuclease inhibitors (RIs) is one of the most important obstacles against the clinical application of RNases. 24 In this regard, various strategies including conjugation with antibodies (Abs), peptide/proteins, and nanoparticles (NPs) have been employed to resolve RIs inhibitory effects.…”

Surveillance of Tumour Development: The Relationship Between Tumour-Associated RNAs and Ribonucleases

“…As a result of RNase A treatment, we also detected an upregulation in carbohydrate metabolism, the stimulation of inositol phosphate cascade and oxidative phosphorylation as well as re-arrangement of apoptosis, transcription, cell cycle control and adhesion processes. Taken together, these data suggest that reorganization of the intracellular network of tumour cells caused by RNase A led to enhancement of energy cascade activity, shift in cancer-related cell growth and dissemination processes, and partial depletion of signalling pathways that have tumour-promoting activity (Mironova et al, 2017).…”

“…Moreover, it was found that RNase A affected the whole transcriptome of murine Lewis lung carcinoma (Mironova et al, 2017) providing the downregulation of 644 transcripts and upregulation of 322 transcripts. Major part of the genes are involved in signalling pathways that maintain energy metabolism, promote cell growth and transformation, modulate the cancer microenvironment and extracellular matrix components as well as stimulate cellular proliferation and differentiation.…”