Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

• Published in: Cell reports (Cambridge) 2014-04, Vol.7 (2), p.488-500
• Main Authors: Wen, Yunfei, Zand, Behrouz, Ozpolat, Bulent, Szczepanski, Miroslaw J., Lu, Chunhua, Yuca, Erkan, Carroll, Amy R., Alpay, Neslihan, Bartholomeusz, Chandra, Tekedereli, Ibrahim, Kang, Yu, Rupaimoole, Rajesha, Pecot, Chad V., Dalton, Heather J., Hernandez, Anadulce, Lokshin, Anna, Lutgendorf, Susan K., Liu, Jinsong, Hittelman, Walter N., Chen, Wen Y., Lopez-Berestein, Gabriel, Szajnik, Marta, Ueno, Naoto T., Coleman, Robert L., Sood, Anil K.
• Format: Article
• Language: English
• Subjects: Apoptosis Regulatory Proteins - metabolism; Autophagy; Beclin-1; Biomarkers, Tumor - metabolism; Carcinoma - diagnosis; Carcinoma - metabolism; Cell Death; Cell Line, Tumor; Female; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - metabolism; Ovarian Neoplasms - diagnosis; Ovarian Neoplasms - metabolism; Phosphoproteins - metabolism; Prolactin - antagonists & inhibitors; Prolactin - metabolism; Prolactin - pharmacology; Protein Kinase C - metabolism; Receptors, Prolactin - metabolism; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.03.009

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. [Display omitted] •PRLR antagonism by G129R inhibits growth of ovarian cancer or cancer spheroids•Autophagy-related cell death is induced by G129R in cancer spheroids•Pea-15 functions as a tumor suppressor to mediate G129R-induced autophagy•Tumoral PRL/PRLR correlates inversely with autophagic factors in clinical samples 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.