LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer.

Autor: Tang W; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.; Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210028, Nanjing, China., Ramasamy K; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Pillai SMA; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Santhamma B; Evestra, Inc., San Antonio, TX, 78245, USA., Konda S; Evestra, Inc., San Antonio, TX, 78245, USA., Pitta Venkata P; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Blankenship L; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Liu J; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.; Department of Oncology, Xiangya Hospital, Central South University, 410008, Hunan, China., Liu Z; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.; Department of Oncology, Xiangya Hospital, Central South University, 410008, Hunan, China., Altwegg KA; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Ebrahimi B; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Pratap UP; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Li X; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Valente PT; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Kost E; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Sareddy GR; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Vadlamudi RK; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Nair HB; Evestra, Inc., San Antonio, TX, 78245, USA., Tekmal RR; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Viswanadhapalli S; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. viswanadhapa@uthscsa.edu.; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. viswanadhapa@uthscsa.edu.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2021 Aug 16; Vol. 7 (1), pp. 216. Date of Electronic Publication: 2021 Aug 16.
DOI: 10.1038/s41420-021-00603-z
Abstrakt: Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC 50 in the range of 20-100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.
(© 2021. The Author(s).)
Databáze: MEDLINE
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