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
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.
