As a multifunctional pituitary hormone and cytokine, prolactin (PRL) is not only essential for normal reproduction and maintenance of pregnancy, but is involved in over 300 biological activities. There is increasing evidence that PRL plays a role in a variety of cancers including ovarian cancer. Elevated levels of PRL have been reported in patients with ovarian cancer. Furthermore, increased expression of PRL receptors (PRLr) have been shown in ovarian cancers, signifying the importance of PRL-mediated signaling in ovarian carcinogenesis. Abnormal activities of PRLr-mediated signaling pathways such as MAPK and JAK2/STAT5 lead to tumorigenicity and recurrence. Therefore, inhibition of PRL signaling is implicated as a target in cancer therapy; however, no viable strategies have been identified for blocking PRL during tumor progression. Herein, we report a novel strategy to counteract the activity of PRLr-mediated cellular survival in malignant ovarian cancer cells with autophagic cell death. Prolanta (G129R), an analog of human PRL with a single amino-acid substitution at position 129 Glycine with bulky Arginine, induces adaptive autophagy through antagonism of the PRLr expressed on human ovarian cancer cells (HeyA8 and SKOV3). The mouse ovarian cancer cell IG10, which does not express PRLr, had no induction of autophagy upon Prolanta treatment. We also identified that Prolanta competitively binds to PRLr and partially inhibits the oncogenic signaling pathways mediated by PRLr, including JNK/STAT3, PI-3K/Rac/PAK pathways that can lead to cell proliferation, differentiation and survival. In addition, we observed cell death after Prolanta treatment in 3-D-spheroid models. We explored molecular mechanisms behind this autophagic cell death induced by Prolanta. Through biomarker identification using the reverse phase protein array (RPPA), we revealed a signaling complex regulated by Pea-15, an autophagy activator through JNK-pathway, which was activated by Prolanta. Microarray analysis reported an array of autophagic genes activated by Prolanta. Furthermore, in an orthotopic mouse model, Prolanta treatment with or without a taxane caused significant inhibition of SKOV3 and HeyA8 growth. In summary, Prolanta functions as a molecular antagonist to tumor-associated PRL by inducing adaptive autophagic cell death in human ovarian cancer. These preclinical findings reveal the novelty of Prolanta as an adjuvant therapy for ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2268. doi:1538-7445.AM2012-2268