Prohibitin – At the crossroads of obesity-linked diabetes and cancer

Abstract

Impact statementProhibitin (PHB) is ubiquitously expressed and plays a role in adipocyte-immune cell cross-talk. Both male and female transgenic mice expressing wild-type PHB in adipose tissue and in macrophages are obese, but only males develop diabetes and liver cancer. When the mice express PHB mutated on tyrosine-114 in adipocytes and macrophages, both males and females are still obese, but none develops liver cancer; instead, males develop lymph node tumors. Adipocyte specific functions of PHB are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. Thus, PHB appears to be an important molecule linking obesity, diabetes, and cancer. In addition, this link appears to be affected by sex steroids. Therefore, targeting PHB may lead to a better understanding of the pathogenesis of obesity, diabetes and cancer. AbstractThe promoter of a gene that is selectively expressed in just a few cell types provides unique opportunities to study: (1) the pleiotropic function of a protein in two different cell types including the cell compartment specific function, and (2) the crosstalk between two cell/ tissue types at the systemic level. This is not possible with a ubiquitous or a highly specific gene promoter. The adipocyte protein-2 (aP2) is one such gene. It is primarily expressed in adipocytes, but also selectively in monocytic macrophages and dendritic cells, among various immune cell types. Thus, the adipocyte protein-2 gene promoter provides an opportunity to simultaneously manipulate adipose and immune functions in a transgenic animal. Prohibitin (PHB) is a pleiotropic protein that has roles in both adipocytes and immune cells. Adipocyte specific functions of prohibitin are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. We capitalized on this attribute of prohibitin to explore the crosstalk between adipose and immune functions, and to discern mitochondrial and plasma membrane-associated cell signaling functions of prohibitin, by expressing wild type prohibitin (Mito-Ob) and a phospho-mutant form of prohibitin (m-Mito-Ob) from the protein-2 gene promoter, individually. Both transgenic mice develop obesity in a sex-neutral manner, but develop obesity-related metabolic dysregulation in a male sex-specific manner. Subsequently, the male Mito-Ob mice spontaneously developed type 2 diabetes and liver cancer, whereas the male m-Mito-Ob mice developed lymph node tumors or autoimmune diabetes in a context-dependent manner. This review provides a point of view on the role of prohibitin in mediating sex differences in adipose and immune functions at the systemic level. We discuss the unique attributes of prohibitin and provide a new paradigm in adipose-immune crosstalk mediated through a pleiotropic protein.

Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma

“…Interestingly, as for another protein of this category, APMAP, our data show that IFN-γ expression was minimal in this tumor. This emphasizes the existence of an important link with prohibitin expression and monocytic macrophages and dendritic cells, as this protein is selectively expressed in these cells [ 50 ], but also with the strong immunosuppressive properties of this tumor attested by the low number of infiltrating T-cells and macrophages, and the minimal expression of CXCL10, CCL5, and CCL11. This differential behavior of M5-T1 compared with F4-T2 and F5-T1 was also observed for FIBB, CD44, and VWA5A, in agreement with the fact that both CD44 and VWA5A were interesting markers for detection of the early stages of colon cancer in the plasma [ 51 ].…”

Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

“…PHBs have been related to several age-related diseases like cancer, neurodegenerative and metabolic disorders [116,117,[119][120][121][122]. Loss of PHB decreases resistance to apoptosis [83] and accelerates aging in yeast [123] and mammalian cells [124][125][126].…”

Vascular targeted nanotherapeutic approach for obesity treatment

“…The role and function of PHB in cancer and obesity has been extensively reviewed. [72][73][74][75] PHB is a 30-kDa multifunctional protein that plays a crucial role in cellular processes such as cell proliferation, endoplasmic reticulum (ER) stress, transcription, apoptosis, and tumor suppression. It is expressed in various cellular compartments including the mitochondria, nucleus, ER, the Golgi complex, endosomes, and plasma membrane.…”

“…PHB was reported to be overexpressed in obesity, 16 cancer, and diabetes and could serve as a potential biomarker for therapeutic intervention. 74,78,79 Molecules that bind to PHB in various diseases are also highlighted in Table 1; they include AHP, 16 flavaglines (FLs), 80 and miR-361. 77 These ligands were used to deliver therapy or gene silencing molecules to PHB for the treatment of diseases.…”