Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

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

doi:10.1016/j.celrep.2014.03.009

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

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. ChenGabriel Lopez-Berestein, Marta Szajnik, Naoto T. Ueno, Robert L. Coleman, Anil K. Sood

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Abstract

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.

Original language	English (US)
Pages (from-to)	488-500
Number of pages	13
Journal	Cell Reports
Volume	7
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2014.03.009
State	Published - Apr 24 2014

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Wen, Y., Zand, B., Ozpolat, B., Szczepanski, M. J., Lu, C., Yuca, E., Carroll, A. R., Alpay, N., Bartholomeusz, C., Tekedereli, I., Kang, Y., Rupaimoole, R., Pecot, C. V., Dalton, H. J., Hernandez, A., Lokshin, A., Lutgendorf, S. K., Liu, J., Hittelman, W. N., ... Sood, A. K. (2014). Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death. Cell Reports, 7(2), 488-500. https://doi.org/10.1016/j.celrep.2014.03.009

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, A, Lutgendorf, SK, Liu, J, Hittelman, WN, Chen, WY, Lopez-Berestein, G, Szajnik, M, Ueno, NT, Coleman, RL & Sood, AK 2014, 'Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death', Cell Reports, vol. 7, no. 2, pp. 488-500. https://doi.org/10.1016/j.celrep.2014.03.009

@article{30ceb34e0e3d4395907a0ad9df0280d7,

title = "Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death",

abstract = "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.",

author = "Yunfei Wen and Behrouz Zand and Bulent Ozpolat and Szczepanski, {Miroslaw J.} and Chunhua Lu and Erkan Yuca and Carroll, {Amy R.} and Neslihan Alpay and Chandra Bartholomeusz and Ibrahim Tekedereli and Yu Kang and Rajesha Rupaimoole and Pecot, {Chad V.} and Dalton, {Heather J.} and Anadulce Hernandez and Anna Lokshin and Lutgendorf, {Susan K.} and Jinsong Liu and Hittelman, {Walter N.} and Chen, {Wen Y.} and Gabriel Lopez-Berestein and Marta Szajnik and Ueno, {Naoto T.} and Coleman, {Robert L.} and Sood, {Anil K.}",

note = "Funding Information: Portions of this work were supported by grants from the US National Institutes of Health (P50CA083639, P50CA098258, CA109298, RC2GM092599, U54 CA151668, CA140933, CA177909, UH2TR000943, T32CA101642, and CA16672), the Department of Defense (OC120547 and OC093416), a Program Project Development Grant from the Ovarian Cancer Research Fund (CPRIT RP110595), the Bettyann Asche Murray Distinguished Professorship, the Chapman Foundation, the Meyer and Ida Gordon Foundation, the Gilder Foundation, the RGK Foundation, and the Blanton-Davis Ovarian Cancer Research Program. Y.W. is supported in part by the NIH 5 P50 SPORE CDP Award CA116199, the Marsha Rivkin Center Pilot Grant, and a research grant from the Foundation for Women{\textquoteright}s Cancer. We thank Robert Langley and Donna M. Reynolds for imaging and Kathryn L. Hale, J. Donald Payne, and Michael Redman for editorial review. ",

year = "2014",

month = apr,

day = "24",

doi = "10.1016/j.celrep.2014.03.009",

language = "English (US)",

volume = "7",

pages = "488--500",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

AU - Wen, Yunfei

AU - Zand, Behrouz

AU - Ozpolat, Bulent

AU - Szczepanski, Miroslaw J.

AU - Lu, Chunhua

AU - Yuca, Erkan

AU - Carroll, Amy R.

AU - Alpay, Neslihan

AU - Bartholomeusz, Chandra

AU - Tekedereli, Ibrahim

AU - Kang, Yu

AU - Rupaimoole, Rajesha

AU - Pecot, Chad V.

AU - Dalton, Heather J.

AU - Hernandez, Anadulce

AU - Lokshin, Anna

AU - Lutgendorf, Susan K.

AU - Liu, Jinsong

AU - Hittelman, Walter N.

AU - Chen, Wen Y.

AU - Lopez-Berestein, Gabriel

AU - Szajnik, Marta

AU - Ueno, Naoto T.

AU - Coleman, Robert L.

AU - Sood, Anil K.

N1 - Funding Information: Portions of this work were supported by grants from the US National Institutes of Health (P50CA083639, P50CA098258, CA109298, RC2GM092599, U54 CA151668, CA140933, CA177909, UH2TR000943, T32CA101642, and CA16672), the Department of Defense (OC120547 and OC093416), a Program Project Development Grant from the Ovarian Cancer Research Fund (CPRIT RP110595), the Bettyann Asche Murray Distinguished Professorship, the Chapman Foundation, the Meyer and Ida Gordon Foundation, the Gilder Foundation, the RGK Foundation, and the Blanton-Davis Ovarian Cancer Research Program. Y.W. is supported in part by the NIH 5 P50 SPORE CDP Award CA116199, the Marsha Rivkin Center Pilot Grant, and a research grant from the Foundation for Women’s Cancer. We thank Robert Langley and Donna M. Reynolds for imaging and Kathryn L. Hale, J. Donald Payne, and Michael Redman for editorial review.

PY - 2014/4/24

Y1 - 2014/4/24

N2 - 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.

AB - 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.

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U2 - 10.1016/j.celrep.2014.03.009

DO - 10.1016/j.celrep.2014.03.009

M3 - Article

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AN - SCOPUS:84899626487

SN - 2211-1247

VL - 7

SP - 488

EP - 500

JO - Cell Reports

JF - Cell Reports

IS - 2

ER -

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

Abstract

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