Stratifin Inhibitor Blocks Lung Cancer Progression

Combining experimental data with a computer-based drug screen, scientists in Japan have found two inhibitors that could slow or stop lung adenocarcinoma tumor growth.

AsianScientist (Mar. 20, 2019) – Scientists in Japan have identified two drugs that may be effective against lung cancer. They reported their findings in the Clinical Cancer Research.

Lung adenocarcinoma is the most common type of lung cancer. Although various targeted drugs have been developed to treat the disease, they do not markedly improve the survival of patients. Part of the explanation for this impasse is a poor understanding of the molecular causes of lung adenocarcinoma during the early stages.

In this study, a research group led by Assistant Professor Aya Shiba-Ishii at the University of Tsubaka, Japan, discovered a molecular mechanism by which lung adenocarcinoma develops. The researchers demonstrated that the culprit is a protein called stratifin which binds to SKP1, a component of a large cellular complex that normally labels molecules in a process called ubiquitination.

Ubiquitination condemns labeled molecules to degradation, but stratifin attaches to SKP1 and prevents SKP1 from performing its labeling function. Hence, errant proteins—some of which may be cancer-causing—build up within cells.

“We used the overexpression of stratifin as well as its blocking by siRNA to clarify the effects on SKP1 in a lung adenocarcinoma cell line,” said Professor Masayuki Noguchi at the University of Tsubaka, a senior author on the study. “The blocking of stratifin meant that SKP1 remained stable and could function in promoting the ubiquitination of errant proteins.”

Based on these findings, the team then undertook computer-based drug screening to find plausible candidates that could inhibit stratifin and prevent its binding to SKP1. The researchers identified four promising candidates that were then narrowed down to two after their efficacy was tested on lung cancer cells.

“Subsequently, we performed additional testing of these two drugs on mice that had been injected with lung cancer cells,” said Shiba-Ishii. “Each drug was administered either the day after cancer cell injection or once tumor establishment had been confirmed. We showed that the two drugs were successful at blocking tumor formation or stopping or reversing the progression of tumors once they had formed.”



The article can be found at: Shiba-Ishii et al. (2019) Stratifin Inhibits SCFFBW7 Formation and Blocks Ubiquitination of Oncoproteins During the Course of Lung Adenocarcinogenesis.

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Source: University of Tsukuba; Photo: Shutterstock.
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