Neuroendocrine‐derived peptides promote prostate cancer cell survival through activation of IGF‐1R signaling

Abstract

Background Neuroendocrine (NE) cells promote the progression of prostate cancer to a castration-resistant state through the production of paracrine growth factors. We have demonstrated this principle using in vitro and in vivo proliferative endpoints; however, the contributions of NE-derived pro-survival factors and anti-apoptosis to this phenomenon have not been thoroughly investigated. Methods Here, we utilized conditioned-medium (CM) from LNCaP cells, engineered to undergo NE differentiation, and examined its effects on PC3 and LNCaP cell survival. Results Statistically significant changes in clonogenic survival, Annexin V staining, PARP cleavage and trypan blue positivity of approximately 2-fold were observed in the presence of NE-derived CM relative to control-CM for both LNCaP and PC3 cells. These changes were partially abrogated by antagonists of the neuropeptides neurotensin, bombesin, and PTHrP. Selective inhibitors of IGF-1R, EGFR or Src caused significant and nearly complete blockade of prostate cancer cell survival due to NE secretions. Similar increases in cell survival were observed for LNCaP or PC3 cells treated with NE-derived medium in the presence of docetaxel. Increased phosphorylation of IGF-1R, following treatment with NE-derived medium, was accompanied by decreased Protein Tyrosine Phosphatase, receptor type F (PTPRF) mRNA and protein levels. Overexpression of PTPRF decreased cell survival, the amplitude and duration of IGF-1R phosphorylation, and enhanced PARP cleavage in the presence of NE-derived medium. Conclusions These data support the hypothesis that NE-derived factors act upon prostate cancer cells to stimulate pro-survival signaling and describe a novel mechanism of cross-talk between NE-derived factors and IGF-1R, mediated in part by PTPRF.

Neuroendocrine differentiation of prostate cancer

“…Experimental evidence has been presented showing that NE tumor cells can promote androgen-independent growth and tumorigenesis, 6 and invasion and metastasis of prostate cancer cells, 7 likely through their secreted products. 8,9 Studies over the years have shown that NE cells secret biogenic amines, neuropeptides and cytokines, while the bulk, non-NE tumor cells express receptors for many of the NE cell products.…”

Hydrogen Sulfide and T-Type Ca²⁺ Channels in Pain Processing, Neuronal Differentiation and Neuroendocrine Secretion

“…In androgen-dependent human prostate cancer LNCaP cells, the neuroendocrine-like differentiation is induced by an elevation of intracellular cAMP levels, androgen deprivation or treatment with interleukin-6 in a subpopulation of the cells [57] . The differentiated cells show androgen-independent properties, and secrete the proliferative neuropeptides such as neurotensin and parathyroid hormone-related peptide (PTHrP), which promote the proliferation of surrounding prostate cancer cells [58,59] . Ca v 3.2 T-type Ca 2+ channels are abundantly expressed in neuroendocrine-like differentiated LNCaP cells, and mediate Ca 2+ -dependent secretion [17,[60][61][62] , while the expression of L-type Ca 2+ channels is not detected in those cells [63] .…”

Parathyroid Hormone-Related Protein and Prostate Cancer

“…В экспериментах с использованием линии клеток рака простаты PC3 показано, что ПТГрП способствует выживанию клеток рака ПЖ путем ак-тивации сигнализации инсулиноподобного факто-ра роста ИФР-1P. Селективный ингибитор ИФР-1P почти полностью блокировал выживание клеток рака простаты РС3 в присутствии доцетаксела [23].…”