American Journal of Physiology-Cell Physiology

POLM variant G312R promotes ovarian tumorigenesis through genomic instability and COL11A1-NF-κB axis

Our research reveals that POLM plays an important role in ovarian cancer development, especially the mutation G312R. We uncover the POLMG312R mutation as a driver of genomic instability in ovarian cancer via aberrant ribonucleotide incorporation. We reveal that POLMG312R upregulates COL11A1 and activates NF-κB signaling, contributing to tumor progression and chemoresistance. This study identifies the POLM-COL11A1-NF-κB axis as a novel oncogenic pathway.

OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3

Ovarian tumor domain-containing protein 6 A (OTUD6A) knockout mice are protected against angiotensin II-induced kidney dysfunction and fibrosis. OTUD6A promotes pathological kidney remodeling and dysfunction by deubiquitinating signal transducer and activator of transcription 3 (STAT3). OTUD6A binds to and removes K63-linked-ubiquitin chains of STAT3 to promote its phosphorylation and activation, and subsequently enhances kidney fibrosis.

Cancer-mesothelial and cancer-macrophage interactions in the ovarian cancer microenvironment

The metastatic ovarian cancer microenvironment is characterized by an intricate interaction network between cancer cells and host cells. This complex heterotypic cancer-host cell crosstalk results in an environment that promotes cancer cell metastasis and treatment resistance, leading to poor patient prognosis and survival. In this review, we focus on two host cell types found in the ovarian cancer microenvironment: mesothelial cells and tumor-associated macrophages. Mesothelial cells make up the protective lining of organs in the abdominal cavity. Cancer cells attach and invade through the mesothelial monolayer to form metastatic lesions. Crosstalk between mesothelial and cancer cells can contribute to metastatic progression and chemotherapy resistance. Tumor-associated macrophages are the most abundant immune cell type in the ovarian cancer microenvironment with heterogeneous subpopulations exhibiting protumor or antitumor functions. Macrophage reprogramming toward a protumor or antitumor state can be influenced by chemotherapy and communication with cancer cells, resulting in cancer cell invasion and treatment resistance. A better understanding of cancer-mesothelial and cancer-macrophage crosstalk will uncover biomarkers of metastatic progression and therapeutic targets to restore chemotherapy sensitivity.

Insights into the tumor-stromal-immune cell metabolism cross talk in ovarian cancer

The ovarian cancer tumor microenvironment (TME) consists of a constellation of abundant cellular components, extracellular matrix, and soluble factors. Soluble factors, such as cytokines, chemokines, structural proteins, extracellular vesicles, and metabolites, are critical means of noncontact cellular communication acting as messengers to convey pro- or antitumorigenic signals. Vast advancements have been made in our understanding of how cancer cells adapt their metabolism to meet environmental demands and utilize these adaptations to promote survival, metastasis, and therapeutic resistance. The stromal TME contribution to this metabolic rewiring has been relatively underexplored, particularly in ovarian cancer. Thus, metabolic activity alterations in the TME hold promise for further study and potential therapeutic exploitation. In this review, we focus on the cellular components of the TME with emphasis on 1) metabolic signatures of ovarian cancer; 2) understanding the stromal cell network and their metabolic cross talk with tumor cells; and 3) how stromal and tumor cell metabolites alter intratumoral immune cell metabolism and function. Together, these elements provide insight into the metabolic influence of the TME and emphasize the importance of understanding how metabolic performance drives cancer progression.

Evolving roles of activins and inhibins in ovarian cancer pathophysiology

Activins and inhibins are unique members of the transforming growth factor-β (TGFβ) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.

Impact of the histone deacetylase inhibitor trichostatin A on active uptake, volume-sensitive release of taurine, and cell fate in human ovarian cancer cells

The histone deacetylase inhibitor trichostatin A (TSA) reduces cell viability in cisplatin-sensitive (A2780WT) and cisplatin-resistant (A2780RES) human ovarian cancer cells due to progression of apoptosis (increased caspase-9 activity), autophagy (increased LC3-II expression), and cell cycle arrest (increased p21 expression). The TSA-mediated effect on p21 and caspase-9 is mainly p53 independent. Cisplatin increases DNA-damage (histone H2AX phosphorylation) in A2780WT cells, whereas cisplatin, due to reduced uptake [inductively coupled-plasma-mass spectrometry (Pt) analysis], has no DNA-damaging effect in A2780RES cells. TSA has no effect on cisplatin accumulation or cisplatin-induced DNA-damage in A2780WT/A2780RES cells. Tracer technique indicates that TSA inhibits the volume-sensitive organic anion channel (VSOAC) in A2780WT/A2780RES cells and that the activity is restored by exogenous H2O2. As TSA reduces NOX4 mRNA accumulation and concomitantly increases catalase mRNA/protein accumulation, we suggest that TSA increases the antioxidative defense in A2780 cells. Inhibition of the kinase mTOR (rapamycin, palomid, siRNA), which is normally associated with cell growth, reduces VSOAC activity synergistically to TSA. However, as TSA increases mTOR activity (phosphorylation of 4EBP1, S6 kinase, S6, ULK1, SGK1), the effect of TSA on VSOAC activity does not reflect the shift in mTOR signaling. Upregulation of the protein expression and activity of the taurine transporter (TauT) is a phenotypic characteristic of A2780RES cells. However, TSA reduces TauT protein expression in A2780RES cells and activity to values seen in A2780WT cells. It is suggested that therapeutic benefits of TSA in A2780 do not imply facilitation of cisplatin uptake but more likely a synergistic activation of apoptosis/autophagy and reduced TauT activity.