Phosphorylation of STAT1 serine 727 enhances platinum resistance in uterine serous carcinoma

Abstract

Uterine serous carcinoma (USC) is a highly aggressive histological subtype of endometrial cancers harboring highly metastatic and chemoresistant features. Our previous study showed that STAT1 is highly expressed in USC and acts as a key molecule that is positively correlated with tumor progression, but it remains unclear whether STAT1 is relevant to the malicious chemorefractory nature of USC. In the present study, we investigated the regulatory role of STAT1 toward platinum-cytotoxicity in USC. STAT1 suppression sensitized USC cells to increase cisplatin-mediated apoptosis (p < 0.001). Furthermore, phosphorylation of STAT1 was prominently observed on serine-727 (pSTAT1-Ser727), but not on tyrosine-701, in the nucleus of USC cells treated with cisplatin. Mechanistically, the inhibition of pSTAT1-Ser727 by dominant-negative plasmid elevated cisplatin-mediated apoptosis by increasing intracellular accumulation of cisplatin through upregulation of CTR1 expression. TBB has an inhibitory effect on casein kinase 2 (CK2), which phosphorylate STAT1 at serine residues. Sequential treatment with TBB and cisplatin on USC cells greatly reduced nuclear pSTAT1-Ser727, enhanced intracellular accumulation of cisplatin, and subsequently increased apoptosis. Tumor load was significantly reduced by combination therapy of TBB and cisplatin in in vivo xenograft models (p < 0.001). Our results collectively suggest that pSTAT1-Ser727 may play a key role in platinum resistance as well as tumor progression in USC. Thus, targeting the STAT1 pathway via CK2 inhibitor can be a novel method for attenuating the chemorefractory nature of USC.

In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients

“…For PD-L1, p-STAT1-and p-EGFR-positive tumor cells were counted as double-positive cells with cytokeratin. To analyze the IHC results, a semi-quantitative method was employed based on previous reports [34,35]. Specifically, the IHC scores for p-EGFR and p-STAT1 were evaluated on a scale of 0-4 (0, <5%; 1, 5-25%; 2, 25-50%; 3, 50-75%; 4, >75%).…”

Expression of STAT family and its potency to prognosis in uterine corpus endometrial carcinoma

“…According to the reports, in UCEC, abnormal STAT1 acted as an oncogene driver positively correlated with tumor progression such as tumorigenicity, proliferation, anchorage-independent growth and invasion (Kharma et al 2014), and could enhance platinum-resistance to induce poor clinical outcome (Zeng et al 2019). Aberrant-activation of STAT3 in UCEC was able to enhance the UCEC cells proliferation, anchorage-independent and xenograft growth ability, and promoted EMT ability (Chen et al 2007;Chu et al 2018;Guo et al 2011;Tang et al 2010).…”