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Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

Wen, Y and Zand, B and Ozpolat, B and Szczepanski, MJ and Lu, C and Yuca, E and Carroll, AR and Alpay, N and Bartholomeusz, C and Tekedereli, I and Kang, Y and Rupaimoole, R and Pecot, CV and Dalton, HJ and Hernandez, A and Lokshin, A and Lutgendorf, SK and Liu, J and Hittelman, WN and Chen, WY and Lopez-Berestein, G and Szajnik, M and Ueno, NT and Coleman, RL and Sood, AK (2014) Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death. Cell Reports, 7 (2). 488 - 500.

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Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism forcell 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 inclinical 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. © 2014 The Authors.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Wen, Y
Zand, B
Ozpolat, B
Szczepanski, MJ
Lu, C
Yuca, E
Carroll, AR
Alpay, N
Bartholomeusz, C
Tekedereli, I
Kang, Y
Rupaimoole, R
Pecot, CV
Dalton, HJ
Hernandez, A
Lokshin, Alokshina@pitt.eduLOKSHINA
Lutgendorf, SK
Liu, J
Hittelman, WN
Chen, WY
Lopez-Berestein, G
Szajnik, M
Ueno, NT
Coleman, RL
Sood, AK
Centers: Other Centers, Institutes, Offices, or Units > Hillman Cancer Center
Date: 24 April 2014
Date Type: Publication
Journal or Publication Title: Cell Reports
Volume: 7
Number: 2
Page Range: 488 - 500
DOI or Unique Handle: 10.1016/j.celrep.2014.03.009
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Date Deposited: 01 Jun 2015 21:49
Last Modified: 04 Feb 2019 15:58


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