Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism.

BACKGROUND: Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. METHODS: Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. RESULTS: Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. CONCLUSIONS: CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

Contrast-Enhanced Ultrasonography for Transabdominal and Transrectal Ultrasound in Staging Cervical Cancer: A Reliability Study.

OBJECTIVE: This retrospective study aimed to evaluate the consistency of transrectal contrast-enhanced ultrasonography (TR-CEUS) with post-operative pathology and the value of contrast-enhanced ultrasonography (CEUS) in staging surgically treated cervical cancer when combined with conventional ultrasonography (US). METHODS: From October 2020 to March 2023, hospitalized patients with stage IB and II cervical cancer confirmed by total hysterectomy were consecutively enrolled. The standard images of US and CEUS by transabdominal (TA-US/CEUS) and transrectal (TR-US/CEUS) approaches and magnetic resonance imaging (MRI) were acquired, on which the size and stage of the tumors were evaluated, and the consistency of results with the pathological specimen was analyzed. RESULTS: Thirty-nine patients with cervical cancer were finally enrolled in this study. The results showed that CEUS significantly improved the reliability of TA-US in evaluating tumor diameter; the intraclass correlation coefficient (ICC) was from 0.672 to 0.735. TR-US indicated good reliability with or without the addition of CEUS (ICC = 0.796 and 0.780). In terms of tumor staging, CEUS improved the consistency of transabdominal (weighted κ values from 0.689 to 0.731) and transrectal staging of tumors (κ from 0.758 to 0.785), and the staging of TR-US combined with TR-CEUS had the highest consistency with post-operative results, similar to MRI (κ, respectively 0.785 and 0.789). CEUS can reflect the heterogeneity of the tumor. Heterogeneous enhancement and perfusion defects were more common in >2 cm cervical cancer (50%, 20/40 and 52.5%, 21/40), respectively, and perfusion defects were more common in moderately to poorly differentiated tumors (66.67%, 20/30). CONCLUSION: For stage IB and IIA cervical cancer, CEUS can aid in assessing the International Federation for Gynecology and Obstetrics staging of tumors alongside TA-US and TR-US. The combination of TR-US and TR-CEUS has shown good consistency with pathology in the staging of cervical cancer, comparable to that of MRI.

Artesunate-induced ATG5-related autophagy enhances the cytotoxicity of NK92 cells on endometrial cancer cells via interactions between CD155 and CD226/TIGIT.

Uterine corpus endometrial carcinoma (UCEC) is the most prevalent gynecologic cancer in developed countries and lacks efficient therapeutic strategies. Artesunate (ART), a well-modified derivate of artemisinin, exerts potent anti-cancer effects apart from its classical anti-malaria feature. Autophagy is a universal double-edged process in cell survival, and CD155 is a novel immune checkpoint highly expressed in numerous cancers. However, the relationships among ART, autophagy, and CD155 remain unclear in UCEC. In this study, we discovered that ART not only inhibited proliferation and migration, promoted apoptosis, but also induced autophagy in UCEC cells. Meanwhile, ART-induced autophagy elevated the level of CD155 in UCEC cells, thereby enhancing the cytotoxicity of natural killer cell line (NK92) by modulating the interactions between CD155 and its receptors in NK92 cells via upregulation of co-stimulator CD226 and downregulation of co-inhibitor TIGIT. Additionally, ART regulated CD155 partially via ATG5, and knockdown of ATG5 dampened the expression of CD155 in UCEC cells, thus decreasing the cytotoxicity of NK92 cells. Therefore, this study demonstrated the dual anti-cancer effects of ART as it could induce cell-killing directly and indirectly, which provides novel insights into the anti-cancer mechanisms of ART on UCEC.