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Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy. Proc Natl Acad Sci U S A 2020 02 18;117(7):3627-3636

Date

02/06/2020

Pubmed ID

32019878

Pubmed Central ID

PMC7035473

DOI

10.1073/pnas.1914153117

Scopus ID

2-s2.0-85079538992   1 Citation

Abstract

The chaperone protein SmgGDS promotes cell-cycle progression and tumorigenesis in human breast and nonsmall cell lung cancer. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, facilitate the activation of oncogenic members of the Ras and Rho families of small GTPases through membrane trafficking via regulation of the prenylation pathway. SmgGDS-607 interacts with newly synthesized preprenylated small GTPases, while SmgGDS-558 interacts with prenylated small GTPases. We determined that cancer cells have a high ratio of SmgGDS-607:SmgGDS-558 (607:558 ratio), and this elevated ratio is associated with reduced survival of breast cancer patients. These discoveries suggest that targeting SmgGDS splicing to lower the 607:558 ratio may be an effective strategy to inhibit the malignant phenotype generated by small GTPases. Here we report the development of a splice-switching oligonucleotide, named SSO Ex5, that lowers the 607:558 ratio by altering exon 5 inclusion in SmgGDS pre-mRNA (messenger RNA). Our results indicate that SSO Ex5 suppresses the prenylation of multiple small GTPases in the Ras, Rho, and Rab families and inhibits ERK activity, resulting in endoplasmic reticulum (ER) stress, the unfolded protein response, and ultimately apoptotic cell death in breast and lung cancer cell lines. Furthermore, intraperitoneal (i.p.) delivery of SSO Ex5 in MMTV-PyMT mice redirects SmgGDS splicing in the mammary gland and slows tumorigenesis in this aggressive model of breast cancer. Taken together, our results suggest that the high 607:558 ratio is required for optimal small GTPase prenylation, and validate this innovative approach of targeting SmgGDS splicing to diminish malignancy in breast and lung cancer.

Author List

Brandt AC, McNally L, Lorimer EL, Unger B, Koehn OJ, Suazo KF, Rein L, Szabo A, Tsaih SW, Distefano MD, Flister MJ, Rigo F, McNally MT, Williams CL

Authors

Mark T. McNally PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Breast Neoplasms
Carcinogenesis
Cell Line, Tumor
Female
Guanine Nucleotide Exchange Factors
Humans
Lung Neoplasms
Male
Mice
Monomeric GTP-Binding Proteins
Protein Isoforms
Protein Prenylation
RNA Splicing
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a