SLFN11’s surveillance part in protein homeostasis

On July 25^th, 2022, a new study perspective called “SLFN11’s surveillance role in protein homeostasis” was published in Volume 9 of Oncoscience.

Video Credit: Impact Journals LLC

In eukaryotes, the endoplasmic reticulum (ER) is the organelle that generates useful proteins. Although increased protein synthesis frequently results in protein misfolding, ER stress and reciprocal activation of the unfolded protein response (UPR) are the results. The ubiquitin-proteasome system (UPS) and ER stress-associated protein degradation (ERAD) pathways eliminate immature proteins.

By reducing the proteotoxic stress brought on by protein synthesis and maturation, the authors of this research point of view (Yasuhisa Murai, Ukhyun Jo, Yasuhiro Arakawa, Naoko Takebe, and Yves Pommier) from Hirosaki University Graduate School of Medicine and the National Cancer Institute have recently shown that Schlafen11 (SLFN11) acts as a monitoring component for protein homeostasis.

A group of genes in human cells known as SLFN5, SLFN11, SLFN12, SLFN12L, SLFN13, and SLFN14 are together referred to as the “schlafen” gene family. SLFN11, a member of the SLFN family, has been recognized as a crucial factor in the cytotoxicity of anticancer drugs that target DNA replication in a variety of cancer types.

Under replication stress, SLFN11 is attracted to broken replication forks. By encouraging the destabilization of the Cdc45-Mcm2-7-GINS (CMG) helicase complex, degrading CDT1, modifying chromatin, and triggering immediate early genes, it irreversibly prevents replication. Chemoresistance is brought on by it not being expressed in about 50% of cancer cells.

“SLFN11 also plays a pivotal role in inhibiting viral infection and tumorigenesis,” the researchers say.

Scientists recently discovered that TAK-243 (MLN7243), a first-in-class inhibitor of the ubiquitin-activating enzyme UBA1 (also known as UBE1), preferentially reduces cell growth of SLFN11 deficient cancer cells by screening the NCATS chemical library, including 1978 molecules. TAK-243 causes ER and proteotoxic stress and forms irreversible ubiquitin adducts with free ubiquitin, which kills cancer cells.

“We also found that cancer cells that do not express SLFN11 exhibit increased global protein ubiquitylation, ER stress, and UPR compared to SLFN11-proficient cells.”

Greater activation of the UPR transducers PERK, phosphorylated eIF2, phosphorylated IRE1, and ATF6 was linked to a higher vulnerability of SLFN11-deficient cells to TAK-243.

The scientists’ findings suggest that the expression status of SLFN11 might be used to anticipate the therapeutic value of TAK243 in cancer treatment, offering that phase 1 clinical trials with this drug are currently being conducted in patients with advanced solid tumors and blood cancers (NCT02045095 and NCT03816319).

The method of action was determined by the scientists, who found that TAK-243-induced proteotoxic stress prevents DNA replication by encouraging Claspindependent CHK1 phosphorylation autonomous of ATR, RPA, and -H2AX activation.

Additionally, they discovered connections between SLFN11 and molecules involved in protein folding as well as translation initiation factors (EIF3A, EIF3B, EIF3D, EIF3E, EIF3F, EIF3H, EIF3L, EIF3M, and EIF4B) / (TCP1, CCT2, CCT3, CCT4, CCT5, CCT6A, CCT7, and CCT8).

“Taken together, our findings suggest that SLFN11 plays a role in protein homeostasis and that lack of SLFN11 expression makes cells vulnerable to anticancer drugs inducing ER and proteotoxic stress.”

SLFN11 is expressed in both immunological and regular human brain cells, not just cancer cells, according to a recent comprehensive immunohistochemical and RNA expression investigation. Numerous human diseases, including atherosclerosis, diabetes, Alzheimer’s, and Parkinson’s disease, can be brought on by unchecked ER stress.

Given that SLFN11 regulates cellular protein ubiquitin adducts and is involved in protein homeostasis, SLFN11 dysfunction may be linked to illnesses other than cancer in humans. Additionally, the change of SLFN11 through control of immunological response and inflammation may be connected to immune insufficiency.

According to a recent study, the IFN-JAK pathway and its downstream MAPK (AKT/ERK)-ETS pathway control the production of SLFN11. According to organoid models and patient samples of ulcerative colitis, SLFN11 expression is known to fluctuate throughout the differentiation of B-cell-derived malignancies and is connected to chronic intestinal mucosal inflammation and excessive apoptosis.

Researchers further conclude, “These observations suggest that SLFN11 works as a co-regulator of immune cells and as an indicator of chronic inflammation. Therefore, further studies are warranted to investigate the role of SLFN11 expression in human autoimmune and inflammatory diseases and as a predictor biomarker of response for patients treated with TAK-243.”