P-MAPA and IL-12 Differentially Regulate Proteins Associated with Ovarian Cancer Progression: A Proteomic Study

Abstract

To investigate the potential role of immunotherapies in the cellular and molecular mechanisms associated with ovarian cancer (OC), we applied a comparative proteomic toll using protein identification combined with mass spectrometry. Herein, the effects of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) were tested alone or in combination in human SKOV-3 cells. The doses and period were defined based on a previous study, which showed that 25 μg/mL P-MAPA and 1 ng/mL IL-12 are sufficient to reduce cell metabolism after 48 h. Indeed, among 2,881 proteins modulated by the treatments, 532 of them were strictly concordant and common. P-MAPA therapy upregulated proteins involved in tight junction, focal adhesion, ribosome constitution, GTP hydrolysis, semaphorin interactions, and expression of SLIT and ROBO, whereas it downregulated ERBB4 signaling, toll-like receptor signaling, regulation of NOTCH 4, and the ubiquitin proteasome pathway. In addition, IL-12 therapy led to upregulation of leukocyte migration, tight junction, and cell signaling, while cell communication, cell metabolism, and Wnt signaling were significantly downregulated in OC cells. A clear majority of proteins that were overexpressed by the combination of P-MAPA with IL-12 are involved in tight junction, focal adhesion, DNA methylation, metabolism of RNA, and ribosomal function; only a small number of downregulated proteins were involved in cell signaling, energy and mitochondrial processes, cell oxidation and senescence, and Wnt signaling. These findings suggest that P-MAPA and IL-12 efficiently regulated important proteins associated with OC progression; these altered proteins may represent potential targets for OC treatment in addition to its immunoadjuvant effects.

RNA m6A modifications regulate crosstalk between tumor metabolism and immunity

“…Secondly, alterations in DC‐secreted cytokines can alter the metabolic activity of other cells as illustrated by IL‐12 serving to activate lymphocytes and stimulate IFN‐γ secretion. Consistently, proteomic studies reported that P‐MAPA and IL‐12 were found to reduce metabolic activity of SKOV‐3 ovarian cancer cells (Júnior et al, 2019) and in breast cancer, IL‐12 promotes the upregulation of the autophagy‐related protein LC3 to promote autophagy (Lin et al, 2017). Together this suggests that IL‐12 blocks some synthetic activities in cancer cells, triggering increased autophagy to compensate, but this notion requires experimental validation.…”

An Integrated Approach to Protein Discovery and Detection From Complex Biofluids

“…This article contains supplemental data ( 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ).…”

Plectin in Cancer: From Biomarker to Therapeutic Target

“…IHC staining demonstrated that plectin only localized to viable tumor regions; thus, further study is warranted to explore if decreased plectin expression is due to increased tumor necrosis or if plectin expression plays a functional role in cell survival after treatment with a vascular disrupting agent [ 44 ]. Moreover, proteomic analysis with ovarian cancer SKOV3 cells revealed reduced plectin expression after treatment with immunotherapies, protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA), and interleukin-12 as single agents or in combination [ 130 ]. The clinical utility of this association remains unknown.…”