Oncogenic Proteomics Approaches for Translational Research and HIV-Associated Malignancy Mechanisms

Abstract

Recent advances in the field of proteomics have allowed extensive insights into the molecular regulations of the cell proteome. Specifically, this allows researchers to dissect a multitude of signaling arrays while targeting for the discovery of novel protein signatures. These approaches based on data mining are becoming increasingly powerful for identifying both potential disease mechanisms as well as indicators for disease progression and overall survival predictive and prognostic molecular markers for cancer. Furthermore, mass spectrometry (MS) integrations satisfy the ongoing demand for in-depth biomarker validation. For the purpose of this review, we will highlight the current developments based on MS sensitivity, to place quantitative proteomics into clinical settings and provide a perspective to integrate proteomics data for future applications in cancer precision medicine. We will also discuss malignancies associated with oncogenic viruses such as Acquire Immunodeficiency Syndrome (AIDS) and suggest novel mechanisms behind this phenomenon. Human Immunodeficiency Virus type-1 (HIV-1) proteins are known to be oncogenic per se, to induce oxidative and endoplasmic reticulum stresses, and to be released from the infected or expressing cells. HIV-1 proteins can act alone or in collaboration with other known oncoproteins, which cause the bulk of malignancies in people living with HIV-1 on ART.

Keywords: HIV-associated malignancies; biomarkers; cancer; co-morbidity; mass spectrometry; quantitative proteomics.

Figure 2

Mechanistic representation of viral malignancy effects triggered by HIV-1 gp120. HIV-1-infected cells infect by using gp120 capacity to induce oxidative, ER stress and glycolytic responses. Gp120 increases free radical production from monocytes and macrophages, which can induce ROS. In astrocytes, ROS production is enhanced using several signaling methods, specifically with cytochrome CYP2E1, NOX2 and NOX4, and the Fenton–Weiss–Haber reaction. ROS-mediated gp120 effects directly activate Twist [145], subsequently modulating Nrf2, and thereby stimulating antioxidant enzymes such as HO1 and Nqol1. In addition, Twist leads to the regulation of Snail, which serves as a transcriptions factor. Both transcription factors, Twist and Snail, are involved in epithelial-to-mesenchymal transduction (EMT), inducing metastasis. The effects of ROS extend towards DNA, lipid, and tissue damage in neighboring cells. Therefore, DNA damage promotes the malignant transformation of normal cells while propagating cancer cells [146]. Gp120 also increases the rate in glycolytic metabolism leading to proliferation, survival, lipid, and protein synthesis [117]. In addition, gp120 triggers ER stress to correct the proper folding of proteins, subsequently activating UPR markers [118]. Figure arrow legends: blue arrows—Process leading to ROS; purple arrows—UPR and ER stress-induced pathways; and green arrows—Metabolic response triggered during HIV-1 infection.

Figure 3

Schematic representation of signaling events for oncological and HIV-associated malignancies. RTKs are crucial regulators of cancer survivability while also corresponding to drug resistances. This allows recruiting adaptor proteins to signal into branching pathways. Mainly the Akt and Ras. CD4+ cells can influence cell survival through CXCR4/CCR5. There is an activation of multiple phosphorylated tyrosine residues that serve as docking platforms through the phosphotyrosine binding (PTB) domain of RTK to regulate a wide range of signaling complexes that benefit cancer-mediated growth. Simultaneously, stress factors such as HIV-1 infection induces UPR and leads to the recruitment of GRP78 for proper folding [117,118]. The endoplasmic reticulum sensors PERK, IRE1α, and ATF6 are no longer inhibited by GRP78, which halts protein translation, the splicing of X-Box Binding Protein 1 (XBP1), and the cleavage of ATF6. The precedence for these oncogenic and metabolic activities influences the tumor microenvironment and results in a favorable cycle of proliferation, angiogenesis, chemoresistance, metastasis, and immune evasion.

Figure 4

Natural compounds as treatments for cancer and HIV-associated malignancies using an ER stress-induced response. Cancer cells are being targeted using promising natural compounds as a mean of therapeutic treatment to revert cancer-mediated growth through chronic ER stress. Acute ER stress, on the other hand, promotes survival and proliferation in malignant cells. These compounds have unique anticancer potentials and are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation.

Figure 1

Diagram depicting quantitative proteomic workflow using tumor and HIV-infected tissue samples. (A) Flowchart illustrating proteomic strategies for biomarkers discovery in clinical cancer with three main types of samples: tumor tissue, body fluids, and cell line cultures. Tumor samples are micro-dissected using LCM microscope. Individual cells are harvested from a complex tissue in situ, lysed, followed by protein extraction/quantification, electrophoresis/staining to protein digestion, peptide recovery, and mass spectrometry. (B) Summary of prominent quantitative proteomics techniques that are used in sample preparation. Unlabeled methods consist of ion peak intensity and spectral counter, while labeled techniques are classified by metabolic and chemical labeling. Image created with BioRender.