Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

Yunfei Wen; Behrouz Zand; Bulent Ozpolat; Miroslaw J. Szczepanski; Chunhua Lu; Erkan Yuca; Amy R. Carroll; Neslihan Alpay; Chandra Bartholomeusz; Ibrahim Tekedereli; Yu Kang; Rajesha Rupaimoole; Chad V. Pecot; Heather J. Dalton; Anadulce Hernandez; Anna Lokshin; Susan K. Lutgendorf; Jinsong Liu; Walter N. Hittelman; Wen Y. Chen; Gabriel Lopez-Berestein; Marta Szajnik; Naoto T. Ueno; Robert L. Coleman; Anil K. Sood

Cell Reports (Apr 2014)

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

Yunfei Wen,
Behrouz Zand,
Bulent Ozpolat,
Miroslaw J. Szczepanski,
Chunhua Lu,
Erkan Yuca,
Amy R. Carroll,
Neslihan Alpay,
Chandra Bartholomeusz,
Ibrahim Tekedereli,
Yu Kang,
Rajesha Rupaimoole,
Chad V. Pecot,
Heather J. Dalton,
Anadulce Hernandez,
Anna Lokshin,
Susan K. Lutgendorf,
Jinsong Liu,
Walter N. Hittelman,
Wen Y. Chen,
Gabriel Lopez-Berestein,
Marta Szajnik,
Naoto T. Ueno,
Robert L. Coleman,
Anil K. Sood

Affiliations

Yunfei Wen: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Behrouz Zand: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Bulent Ozpolat: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Miroslaw J. Szczepanski: Department of Otolaryngology, Medical University of Warsaw, Warsaw 02-091, Poland
Chunhua Lu: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Erkan Yuca: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Amy R. Carroll: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Neslihan Alpay: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Chandra Bartholomeusz: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Ibrahim Tekedereli: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Yu Kang: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Rajesha Rupaimoole: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Chad V. Pecot: Department of Thoracic, Head and Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Heather J. Dalton: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Anadulce Hernandez: Department of Biology and Biochemistry, University of Houston, Houston, TX 77024, USA
Anna Lokshin: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
Susan K. Lutgendorf: Departments of Psychology and Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA
Jinsong Liu: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Walter N. Hittelman: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Wen Y. Chen: Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA
Gabriel Lopez-Berestein: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Marta Szajnik: Department of Gynecologic Oncology, Poznan University of Medical Sciences, Poznan 60-535, Poland
Naoto T. Ueno: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Robert L. Coleman: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Anil K. Sood: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author

Journal volume & issue: Vol. 7, no. 2
pp. 488 – 500

Abstract

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Summary: Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized G129R, an antagonist peptide of PRL, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced the accumulation of redundant autolysosomes in 3D cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a noncanonical beclin-1-independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide an understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications. : Pharmacological manipulation of autophagy represents a new therapeutic opportunity for cancer. Wen et al. show that blockade of the tumoral PRL/PRLR axis with an antagonist, G129R, induces prolonged autophagy. This inducible autophagy is sustained by the PEA-15 and PKC zeta interactome and leads to type II programmed cell death. There was an inverse correlation between tumoral PRL/PRLR expression and survival of ovarian cancer patients. This study reveals a previously unrecognized mechanism related to targeting the tumoral PRL/PRLR pathway.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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