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Cell Rep. 2014 Apr 24;7(2):488-500. doi: 10.1016/j.celrep.2014.03.009. Epub 2014 Apr 3.

Antagonism of tumoral prolactin receptor promotes autophagy-related cell death.

Author information

1
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
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.
3
Department of Otolaryngology, Medical University of Warsaw, Warsaw 02-091, Poland.
4
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Thoracic, Head and Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Biology and Biochemistry, University of Houston, Houston, TX 77024, USA.
8
Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
9
Departments of Psychology and Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
10
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
11
Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA.
12
Department of Gynecologic Oncology, Poznan University of Medical Sciences, Poznan 60-535, Poland.
13
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.
14
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. Electronic address: asood@mdanderson.org.

Abstract

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.

PMID:
24703838
PMCID:
PMC4038960
DOI:
10.1016/j.celrep.2014.03.009
[Indexed for MEDLINE]
Free PMC Article

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