Antagonism of tumoral prolactin receptor promotes autophagy-related cell death.
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.
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yunfei
Y
Wen
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Behrouz
B
Zand
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.
Bulent
B
Ozpolat
Department of Otolaryngology, Medical University of Warsaw, Warsaw 02-091, Poland.
Miroslaw J
MJ
Szczepanski
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chunhua
C
Lu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Erkan
E
Yuca
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Amy R
AR
Carroll
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Neslihan
N
Alpay
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chandra
C
Bartholomeusz
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ibrahim
I
Tekedereli
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yu
Y
Kang
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Rajesha
R
Rupaimoole
Department of Thoracic, Head and Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chad V
CV
Pecot
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Heather J
HJ
Dalton
Department of Biology and Biochemistry, University of Houston, Houston, TX 77024, USA.
Anadulce
A
Hernandez
Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Anna
A
Lokshin
Departments of Psychology and Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Susan K
SK
Lutgendorf
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jinsong
J
Liu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Walter N
WN
Hittelman
Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA.
Wen Y
WY
Chen
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.
Gabriel
G
Lopez-Berestein
Department of Gynecologic Oncology, Poznan University of Medical Sciences, Poznan 60-535, Poland.
Marta
M
Szajnik
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Naoto T
NT
Ueno
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.
Robert L
RL
Coleman
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.
Anil K
AK
Sood
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000175:diagnosis / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011388:Prolactin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011981:Receptors, Prolactin / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D000099221:Protein Kinase C zeta
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011388:Prolactin; D011493:Protein Kinase C; D011981:Receptors, Prolactin; D000099221:Protein Kinase C zeta; C491997:BECN1 protein, human; C092039:PEA15 protein, human; C402398:prolactin, Arg(129)-