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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 7 Issue 2 Pg. 488-500 (Apr 24 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 24703838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Biomarkers, Tumor
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• PEA15 protein, human
• Phosphoproteins
• Receptors, Prolactin
• prolactin, Arg(129)-
• Prolactin
• protein kinase C zeta
• Protein Kinase C

Topics

• Apoptosis Regulatory Proteins (metabolism)
• Autophagy
• Beclin-1
• Biomarkers, Tumor (metabolism)
• Carcinoma (diagnosis, metabolism)
• Cell Death
• Cell Line, Tumor
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Membrane Proteins (metabolism)
• Ovarian Neoplasms (diagnosis, metabolism)
• Phosphoproteins (metabolism)
• Prolactin (antagonists & inhibitors, metabolism, pharmacology)
• Protein Kinase C (metabolism)
• Receptors, Prolactin (metabolism)
• Spheroids, Cellular (drug effects, metabolism)