Phosphorylation of STAT1 serine 727 enhances platinum resistance in uterine serous carcinoma. Issue 6 (22nd June 2019)

• Record Type: Journal Article
• Authors: Zeng, Xiang; Baba, Tsukasa; Hamanishi, Junzo; Matsumura, Noriomi; Kharma, Budiman; Mise, Yuka; Abiko, Kaoru; Yamaguchi, Ken; Horikawa, Naoki; Hunstman, David G.; Mulati, Kumuluzi; Kitamura, Sachiko; Taki, Mana; Murakami, Ryusuke; Hosoe, Yuko; Mandai, Masaki
• Is Part Of: International journal of cancer. Volume 145:Issue 6(2019)
• Page Start: 1635
• Page End: 1647
• Publication Date: 2019-06-22
• Subjects: STAT1 -- pSTAT1‐serine (Ser727) -- casein kinase 2 -- copper transport protein -- uterine serous carcinoma; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32501
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? The molecular mechanisms underlying chemoresistance in uterine serous carcinoma (USC), a rare but highly aggressive subtype of endometrial cancer, remain unclear. This study shows that the prognostic outcome for USC patients with high STAT1 expression is poor and STAT1 is involved in platinum resistance. Mechanistically, cisplatin‐induced STAT1 Ser727 phosphorylation alters cellular platinum accumulation to promote resistance and CK2 inhibitors can suppress STAT1 Ser727 phosphorylation. The results suggest that STAT1 could serve as a biomarker to predict tumor chemoresponse, and premedication with a CK2 inhibitor may represent a potent strategy to increase the efficacy of platinum‐based chemotherapeutics in STAT1‐high USC patients.