Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate

Abstract

Adenylosuccinate lyase (ADSL) is an enzyme that plays important roles in de novo purine synthesis. Although ADSL was reported to be upregulated in various malignancies, such as colorectal, breast, and prostate cancer, as well as gliomas, the mechanism by which elevated ADSL expression contributes to cancer has not been elucidated. We previously performed a shotgun proteomics analysis to characterize specific proteins associated with the properties of the aldehyde dehydrogenase (ALDH)-high cell population, which was reported to be involved in tumorigenic potential, and showed that ADSL expression is upregulated in the ALDH-high population of endometrial cancer. Here, we showed that ADSL is involved in endometrial cancer aggressiveness by regulating expression of killer cell lectin-like receptor C3 (KLRC3), which is a receptor expressed on natural killer cells. Immunohistochemical analysis indicated that ADSL expression increased as endometrioid carcinoma specimens became more poorly differentiated and higher degree of primary tumor progression. Knockdown of ADSL in endometrial cancer cells decreased cell proliferation, migration, and invasive capability, and caused the cells to adopt a more rounded shape. DNA microarray analysis and quantitative real-time PCR showed that KLRC3 expression was decreased in ADSL knockdown cells. Knockdown of KLRC3 in endometrial cancer cells resulted in the same phenotype as knockdown of ADSL. Moreover, fumarate, which could be produced by ADSL and was recently shown to be an oncometabolite, recovered KLRC3 expression in ADSL knockdown cells, suggesting that fumarate produced by ADSL could regulate KLRC3 expression. Our findings indicate that ADSL enhances cell proliferation, migration, and invasive capability through regulation of KLRC3 expression by fumarate.

Serum deprivation‐response protein regulates aldehyde dehydrogenase 1 through integrin‐linked kinase signaling in endometrioid carcinoma cells

“…Adenylsuccinate lyase enhances cell proliferation, migration, and invasion by regulating the effect of the oncometabolite fumarate on killer cell lectin‐like receptor C3 expression. However, depletion of S100A4 or ADSL was not found to affect the expression of ALDH1 . In contrast, we report here that depletion of SDPR severely attenuated ALDH1 expression.…”

“…However, depletion of S100A4 or ADSL was not found to affect the expression of ALDH1. 4 In contrast, we report here that depletion of SDPR severely attenuated ALDH1 expression. We also analyzed the mechanism underlying the effect of SDPR on ALDH1.…”

“…18,19 Although we previously reported the function of S100A4 or ADSL, which were highly expressed in EC cells with high ALDH1 expression, the depletion of S100A4 or ADSL did not affect the expression of ALDH1. 3,4 Among the isolated proteins we previously reported, SDPR is the first found to influence the expression of ALDH1.…”

“…We compared the levels of several proteins in HEC‐1B human EC cells with high ALDH1 expression (ALDH‐hi) vs low ALDH1 expression (ALDH‐lo) using shotgun proteomics. The results indicated that several proteins, such as S100A4 and ADSL, are preferentially expressed in ALDH‐hi cells . Serum deprivation‐response protein is reportedly also preferentially expressed in ALDH‐hi cells …”

“…The results indicated that several proteins, such as S100A4 and ADSL, are preferentially expressed in ALDH-hi cells. 3,4 Serum deprivationresponse protein is reportedly also preferentially expressed in ALDH-hi cells. 3 Serum deprivation-response protein, also known as cavin-2, is a member of the cavin family of proteins.…”