Targeting the Deregulated Spliceosome Core Machinery in Cancer Cells Triggers mTOR Blockade and Autophagy

Abstract

The spliceosome is a large ribonucleoprotein complex that guides pre-mRNA splicing in eukaryotic cells. Here, we determine whether the spliceosome could constitute an attractive therapeutic target in cancer. Analysis of gene expression arrays from lung, breast, and ovarian cancers datasets revealed that several genes encoding components of the core spliceosome composed of a heteroheptameric Sm complex were overexpressed in malignant disease as compared with benign lesions and could also define a subset of highly aggressive breast cancers. siRNA-mediated depletion of SmE (SNRPE) or SmD1 (SNRPD1) led to a marked reduction of cell viability in breast, lung, and melanoma cancer cell lines, whereas it had little effect on the survival of the nonmalignant MCF-10A breast epithelial cells. SNRPE or SNRPD1 depletion did not lead to apoptotic cell death but autophagy, another form of cell death. Indeed, induction of autophagy was revealed by cytoplasmic accumulation of autophagic vacuoles and by an increase in both LC3 (MAP1LC3A) protein conversion and the amount of acidic autophagic vacuoles. Knockdown of SNRPE dramatically decreased mTOR mRNA and protein levels and was accompanied by a deregulation of the mTOR pathway, which, in part, explains the SNRPE-dependent induction of autophagy. These findings provide a rational to develop new therapeutic agents targeting spliceosome core components in oncology. Cancer Res; 73(7); 2247-58. Ó2013 AACR.

Circulating Serum Exosomal miRNAs As Potential Biomarkers for Esophageal Adenocarcinoma

“…Currently, the common housekeeping genes include small nuclear/nucleolar RNAs such as RNU44, RNU48 and RNU6-1, also more commonly known as U6. The spliceosome complex, which catalyzes pre-mRNA splicing, and in which U6 is a key functional component, is frequently deregulated in a wide variety of cancers [30]. Consistent with this and with our findings, it has been shown that serum RNU6-1 levels are differentially expressed in serum from individuals with breast cancer compared to healthy controls [31].…”

Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication

“…We identified most of the spliceosomal proteins that previously have been shown to be hyperexpressed in ovarian cancer cells (37) (supplemental Table S5). This result was of special interest because Quidville et al demonstrated that some spliceosomal components hyperexpressed in cancer cells participate in the regulation of the PI3K/Akt/mTOR pathway, which is often disturbed in ovarian cancer (38). Thus, spliceosome components are attractive targets for anticancer therapy.…”

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

“…Overexpression of Sm domain spliceosome proteins has been found in a number of malignancies and defines a subset of cancers with aggressive features (Quidville et al 2013). A number of studies have identified frequent and recurrent somatic mutations in spliceosome machinery components such as SF3B1, ZRSR2, U2AF1, and SRSF2 in multiple cancer types.…”