TY - JOUR
T1 - Blockade of the short form of prolactin receptor induces FOXO3a/EIF-4EBP1–mediated cell death in uterine cancer
AU - Wen, Yunfei
AU - Wang, Ying
AU - Chelariu-Raicu, Anca
AU - Stur, Elaine
AU - Liu, Yuan
AU - Corvigno, Sara
AU - Bartsch, Faith
AU - Redfern, Lauren
AU - Zand, Behrouz
AU - Kang, Yu
AU - Liu, Jinsong
AU - Baggerly, Keith
AU - Sood, Anil K.
N1 - Funding Information:
Portions of this work were supported by the Department of Defense Ovarian Cancer Research Program W81XWH2010335 (Y. Wen), NIH Uterine SPORE P50CA098258 (to Y. Wen and A.K. Sood), National Comprehensive Cancer Network (to Y. Wen), Marsha Rivkin Center for Ovarian Cancer Research (to Y. Wen), the NIH P50CA217685 (to A.K. Sood), R35CA209904 (to A.K. Sood), P30CA016672 (used for the Bioinformatics Shared Resource and the Functional Proteomics RPPA Core Facility), the American Cancer Society Research Professor Award (to A.K. Sood), the Frank McGraw Memorial Chair in Cancer Research (to A.K. Sood), and the Blanton-Davis Ovarian Cancer Research Program (to Y. Wen and A.K. Sood). A. Chelariu-Raicu was supported by funds from Deutsche Forschungsgemeinschaft (CH 1733/1-2). E. Stur is supported by Ovarian Cancer Research Alliance (OCRA number FP00006137). In addition, we thank Dr. Walter N. Hittelman at MD Anderson Cancer Center for help with multiphoton confocal imaging, Donald Payne and Michael Redman at Oncolix Inc. for supplying G129R, and Kathryn Hale and Sunita Patterson for their editorial work.
Funding Information:
A.K. Sood reports personal fees from Merck and Kiyatec, stock ownership from BioPath (shareholder), and grants from Esperance and MTrap outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
Portions of this work were supported by the Department of Defense Ovarian Cancer Research Program W81XWH2010335 (Y. Wen), NIH Uterine SPORE P50CA098258 (to Y. Wen and A.K. Sood), National Comprehensive Cancer Network (to Y. Wen), Marsha Rivkin Center for Ovarian Cancer Research (to Y. Wen), the NIH
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contributes to the progression of uterine carcinoma. However, the underlying mechanisms are not well understood, and current means of targeting the PRL/PRLR axis in uterine cancer are limited. Our integrated analyses using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases demonstrated that a short form of PRLR (PRLR_SF) is the isoform predominantly expressed in human uterine cancers; expression of this PRLR_SF was elevated in uterine cancers in comparison with cancer-free uterine tissues. We hypothesized that the overexpression of PRLR_SF in uterine cancer cells contributes, in part, to the oncogenic activity of the PRL/PRLR axis. Next, we employed G129R, an antagonist of human PRL, to block the PRL/PRLR axis in both PTENwt and PTENmut orthotopic mouse models of uterine cancer. In comparison with control groups, treatment with G129R as monotherapy or in combination with paclitaxel resulted in a significant reduction of growth and progression of orthotopic uterine tumors. Results from protein profiling of uterine cancer cells and in vivo tumors revealed a set of new downstream targets for G129R. Our results showed that G129R induced sub-G0 population arrest, decreased nascent protein synthesis, and initiated FOXO3a/EIF-4EBP1–mediated cell death in both PTENwt and PTENmut uterine cancer cells. Collectively, our results show a unique pattern of PRLR_SF expression predominantly in uterine cancer. Moreover, FOXO3a and EIF-4EBP1 are important mediators of cell death following G129R treatment in uterine cancer models.
AB - Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contributes to the progression of uterine carcinoma. However, the underlying mechanisms are not well understood, and current means of targeting the PRL/PRLR axis in uterine cancer are limited. Our integrated analyses using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases demonstrated that a short form of PRLR (PRLR_SF) is the isoform predominantly expressed in human uterine cancers; expression of this PRLR_SF was elevated in uterine cancers in comparison with cancer-free uterine tissues. We hypothesized that the overexpression of PRLR_SF in uterine cancer cells contributes, in part, to the oncogenic activity of the PRL/PRLR axis. Next, we employed G129R, an antagonist of human PRL, to block the PRL/PRLR axis in both PTENwt and PTENmut orthotopic mouse models of uterine cancer. In comparison with control groups, treatment with G129R as monotherapy or in combination with paclitaxel resulted in a significant reduction of growth and progression of orthotopic uterine tumors. Results from protein profiling of uterine cancer cells and in vivo tumors revealed a set of new downstream targets for G129R. Our results showed that G129R induced sub-G0 population arrest, decreased nascent protein synthesis, and initiated FOXO3a/EIF-4EBP1–mediated cell death in both PTENwt and PTENmut uterine cancer cells. Collectively, our results show a unique pattern of PRLR_SF expression predominantly in uterine cancer. Moreover, FOXO3a and EIF-4EBP1 are important mediators of cell death following G129R treatment in uterine cancer models.
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UR - http://www.scopus.com/inward/citedby.url?scp=85094167305&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-19-1026
DO - 10.1158/1535-7163.MCT-19-1026
M3 - Article
C2 - 32737156
AN - SCOPUS:85094167305
SN - 1535-7163
VL - 19
SP - 1943
EP - 1954
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -