bims-lymeca 2022-07-24 papers

Issue of 2022‒07‒24
five papers selected by
Harilaos Filippakis
University of New England

J Cardiovasc Pharmacol. 2022 Jul 18.

Atorvastatin ameliorates doxorubicin-induced cardiomyopathy by regulating the autophagy-lysosome pathway and its upstream regulatory factor transcription factor EB.

Shiliang Jiang, Wan-Ching Chou, Linqing Tao, Zhaoyang Qiu, Ge Gao.

ABSTRACT: Doxorubicin (DOX) is a widely used anticancer drug in clinical practice, and its myocardial toxicity is the main concern in oncotherapy. Statins are commonly used as hypolipidemic drugs. Recent studies have also focused on the effects of statins on autophagy. Autophagy is a process in which cells consume their own cytoplasm or organelles after stimulation, and finally degrade the phagosome in the lysosome. Transcription factor EB (TFEB) is the main factor regulating lysosomal gene transcription and function. We found that atorvastatin increased TFEB protein levels and the ratio of LAMP2/LC3B in the myocardial tissue of mice with doxorubicin-induced cardiomyopathy (DIC). Therefore, we speculated that atorvastatin may improve cardiac function in mice with DIC by increasing the expression of TFEB to enhance lysosomal function and autophagy. This study explored the role of TFEB in DIC and the possible mechanism of atorvastatin in improving DIC and used statins to prevent and treat DIC; various dilated cardiomyopathy and heart failure diseases provide more experimental evidence. All relevant data are within the paper and its Supporting Information files.

DOI: https://doi.org/10.1097/FJC.0000000000001334

Cancer Res. 2022 Jul 22. pii: CAN-22-0121. [Epub ahead of print]

Activating mTOR mutations are detrimental in nutrient-poor conditions.

Agata A Bielska, Caitlin F Harrigan, Yeon Ju Kyung, Quaid Morris, Wilhelm Palm, Craig B Thompson.

The mechanistic target of rapamycin (mTOR) is a key regulator of cell growth that integrates growth factor signaling and nutrient availability and is a downstream effector of oncogenic receptor tyrosine kinases (RTKs) and PI3K/Akt signaling. Thus, activating mTOR mutations would be expected to enhance growth in many tumor types. However, tumor sequencing data has shown that mTOR mutations are enriched only in renal clear cell carcinoma, a clinically hypervascular tumor unlikely to be constrained by nutrient availability. To further define this cancer type-specific restriction, we studied activating mutations in mTOR. All mTOR mutants tested enhanced growth in a cell type agnostic manner under nutrient-replete conditions but were detrimental to cell survival in nutrient-poor conditions. Consistently, analysis of tumor data demonstrated that oncogenic mutations in the nutrient-sensing arm of the mTOR pathway display a similar phenotype and were exceedingly rare in human cancers of all types. Together, these data suggest that maintaining the ability to turn off mTOR signaling in response to changing nutrient availability is retained in most naturally occurring tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0121

Proc Natl Acad Sci U S A. 2022 Jul 19. 119(29): e2203769119

In situ architecture of the lipid transport protein VPS13C at ER-lysosome membrane contacts.

Shujun Cai, Yumei Wu, Andrés Guillén-Samander, William Hancock-Cerutti, Jun Liu, Pietro De Camilli.

VPS13 is a eukaryotic lipid transport protein localized at membrane contact sites. Previous studies suggested that it may transfer lipids between adjacent bilayers by a bridge-like mechanism. Direct evidence for this hypothesis from a full-length structure and from electron microscopy (EM) studies in situ is still missing, however. Here, we have capitalized on AlphaFold predictions to complement the structural information already available about VPS13 and to generate a full-length model of human VPS13C, the Parkinson's disease-linked VPS13 paralog localized at contacts between the endoplasmic reticulum (ER) and endo/lysosomes. Such a model predicts an ∼30-nm rod with a hydrophobic groove that extends throughout its length. We further investigated whether such a structure can be observed in situ at ER-endo/lysosome contacts. To this aim, we combined genetic approaches with cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) to examine HeLa cells overexpressing this protein (either full length or with an internal truncation) along with VAP, its anchoring binding partner at the ER. Using these methods, we identified rod-like densities that span the space separating the two adjacent membranes and that match the predicted structures of either full-length VPS13C or its shorter truncated mutant, thus providing in situ evidence for a bridge model of VPS13 in lipid transport.

Keywords: VPS13; cryo-electron tomography; lipid-transfer protein; membrane contact sites

DOI: https://doi.org/10.1073/pnas.2203769119

Cell Oncol (Dordr). 2022 Jul 22.

Cholesterol homeostasis and cancer: a new perspective on the low-density lipoprotein receptor.

Jia Gu, Neng Zhu, Hong-Fang Li, Tan-Jun Zhao, Chan-Juan Zhang, Duan-Fang Liao, Li Qin.

BACKGROUND: Disturbance of cholesterol homeostasis is considered as one of the manifestations of cancer. Cholesterol plays an essential role in the pleiotropic functions of cancer cells, including mediating membrane trafficking, intracellular signal transduction, and production of hormones and steroids. As a single transmembrane receptor, the low-density lipoprotein receptor (LDLR) can participate in intracellular cholesterol uptake and regulate cholesterol homeostasis. It has recently been found that LDLR is aberrantly expressed in a broad range of cancers, including colon cancer, prostate cancer, lung cancer, breast cancer and liver cancer. LDLR has also been found to be involved in various signaling pathways, such as the MAPK, NF-κB and PI3K/Akt signaling pathways, which affect cancer cells and their surrounding microenvironment. Moreover, LDLR may serve as an independent prognostic factor for lung cancer, breast cancer and pancreatic cancer, and is closely related to the survival of cancer patients. However, the role of LDLR in some cancers, such as prostate cancer, remains controversial. This may be due to the lack of normal feedback regulation of LDLR expression in cancer cells and the severe imbalance between LDLR-mediated cholesterol uptake and de novo biosynthesis of cholesterol.CONCLUSIONS: The imbalance of cholesterol homeostasis caused by abnormal LDLR expression provides new therapeutic opportunities for cancer. LDLR interferes with the occurrence and development of cancer by modulating cholesterol homeostasis and may become a novel target for the development of anti-cancer drugs. Herein, we systematically review the contribution of LDLR to cancer progression, especially its dysregulation and underlying mechanism in various malignancies. Besides, potential targeting and immunotherapeutic options are proposed.

Keywords: Biomarker; Cancer; Cholesterol homeostasis; Low-density lipoprotein receptor; Microenvironment

DOI: https://doi.org/10.1007/s13402-022-00694-5

Nat Commun. 2022 Jul 22. 13(1): 4247

A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer.

Michael R Kelly, Kamila Wisniewska, Matthew J Regner, Michael W Lewis, Andrea A Perreault, Eric S Davis, Douglas H Phanstiel, Joel S Parker, Hector L Franco.

The human genome contains regulatory elements, such as enhancers, that are often rewired by cancer cells for the activation of genes that promote tumorigenesis and resistance to therapy. This is especially true for cancers that have little or no known driver mutations within protein coding genes, such as ovarian cancer. Herein, we utilize an integrated set of genomic and epigenomic datasets to identify clinically relevant super-enhancers that are preferentially amplified in ovarian cancer patients. We systematically probe the top 86 super-enhancers, using CRISPR-interference and CRISPR-deletion assays coupled to RNA-sequencing, to nominate two salient super-enhancers that drive proliferation and migration of cancer cells. Utilizing Hi-C, we construct chromatin interaction maps that enable the annotation of direct target genes for these super-enhancers and confirm their activity specifically within the cancer cell compartment of human tumors using single-cell genomics data. Together, our multi-omic approach examines a number of fundamental questions about how regulatory information encoded into super-enhancers drives gene expression networks that underlie the biology of ovarian cancer.

DOI: https://doi.org/10.1038/s41467-022-31919-8