La clusterina (CLU), también conocida como proteína fijadora de lípidos tipo A2 o apolipoproteína J (ApoJ), SPG2, TRPM-2 o CLU, es una chaperona molecular que se descubrió por primera vez en 1979 en testículos de rata, donde se observó que causaba agregación celular. in vitro [ 1 ]. Esta proteína está presente en los tejidos y fluidos corporales humanos, como la sangre, la saliva, el líquido cefalorraquídeo y el líquido sinovial, que tienen un papel importante en procesos como la adhesión celular, la respuesta inmune y la supervivencia celular [2 , 3 , 4 ] . También se ha demostrado que CLU inhibe la agregación de proteínas bajo estrés celular al unirse a proteínas mal plegadas, lo que resulta en la acumulación de proteínas inactivas pero estabilizadas, que pueden recuperar su funcionalidad con la ayuda de otras chaperonas plegables.5 ]. En situaciones celulares estresantes, como la exposición a fármacos quimioterapéuticos, hipoxia o radiaciones ionizantes, aumentan los niveles de clusterina como parte de su mecanismo de defensa [ 6 ].

El gen CLU humano , ubicado en el cromosoma 8p21-p12, consta de 11 exones y aproximadamente 16 kilobases. CLU produce tres productos de transcripción principales [ 7 ], Variante 1: NM_001831, Variante 2: NR_038335 y Variante 3: NR_045494, que comparten los exones 2 a 11 pero difieren en el exón 1 (1a, 1b, 1c), lo que sugiere que cada variante tiene un sitio de inicio de transcripción distinto.

The first 22 amino acids of this sequence encode a signal that directs translocation of the preprotein to the endoplasmic reticulum (ER), where that sequence is removed and N-glycosylation of 6 asparagine residues occurs, as well as the formation of 4 or 5 disulfide bridges [8]. The protein then translocates to the Golgi apparatus, where it undergoes a more complex glycosylation that promotes its maturation, reaching a weight of 70 to 80 kDa. Subsequently, the highly glycosylated protein is cleaved between residues 227 and 228 and bound by a disulfide bond, leading to the formation of the mature form of the protein or secreted isoform (sCLU). This isoform can be internalized by other cells and stabilize the synthesis of the p53 protein, which is involved in the activation of cell cycle arresting genes, thus can inhibit cell proliferation [9,10] (Figure 1).

In situations where this maturation pathway does not occur, a process known as alternative splicing occurs between exons 1 and 3, resulting in the deletion of exon 2. This produces a protein that lacks the ER translocation signal, generating a non-functional 49 kDa prenuclear isoform (pnCLU). However, under stress, this isoform transforms into a nuclear and functional 55 kDa isoform (nCLU) [8]. The nuclear isoform translocates to the nucleus and, through its binding to the Ku70 protein, promotes cell apoptosis [11,12,13,14] (Figure 1).

On the other hand, there may also be a nearly mature, presecreted 53 KDa isoform (psCLU), which binds to the GRP78 (Bip) chaperone in the ER under stress and translocates to the mitochondrion. There, it binds to the activated form of the Bax protein, which modulates its ability to form homodimers and, in turn, inhibits the formation of Bax-Bak complexes [15]. These complexes, if not inhibited, would induce the apoptotic signaling cascade, demonstrating that clusterin has antiapoptotic activity. Furthermore, when the psCLU isoform is found in the cytoplasm, it can stabilize the Ku70-Bax complex, thus preventing the arrival of Bax into the mitochondria [9]. In the cytoplasm, it can also bind to cytotoxic substances and promote their proteasomal degradation, which further contributes to its antiapoptotic activity [16].

CLU expression can be induced by various factors, such as oxidative stress, chemotherapeutic agents, ionizing and ultraviolet radiation, estrogen, or androgen deprivation in hormone-sensitive tumors, or her2-neu receptor blockade [17,18]. In response to proapoptotic stimuli of various origins, CLU expression increases to protect and enable cell survival. There are two forms of CLU with opposite functions: the sCLU secretory form has a cytoprotective role, whereas the nCLU form can promote cell death [19,20]. Each form of CLU may be subject to its own regulatory pathway.

The regulation of CLU depends not only on the form of the protein, but also on the cell type. In addition to being found in Sertoli cells [21], CLU can be found in a wide variety of cells, such as motor neurons [22], dermal fibroblasts [23] and epithelial cells [24]. CLU expression in these varies considerably and this is thought to be due to both tissue type and different regulatory pathways acting in physiological or pathological situations [2,25]. Various factors, such as TGF-β, NGF (Nerve Growth Factor), EGF (epidermal growth factor), cytokines such as TNF-α and IL-1, IL-2, and IL-6, are involved in the regulation of CLU synthesis [2]. The Wnt signaling pathway and transcription factors such as TCF1, Jak/STAT1 (Signal Transducers and Activators of Transcription 1) and IGF1 (Insulin-Like Growth Factor 1) also play a role in CLU expression [26,27]. In addition, ATM (Ataxia Telangiectasia-Mutated) has been found to act as a sensor of DNA damage, being necessary for the induction of the IGF1-sCLU axis after ionizing radiation [28]. On the other hand, Ha-Ras and c-myc oncogenes can downregulate CLU expression [10]. CLU regulation is mediated by several elements present in the CLU promoter region, such as AP-1 (Activator Protein-1), AP-2 (Activator Protein-2), SP-1 (Stimulatory Element-1), CLE (Clusterin Element), heat shock element (HSE)-like sequences, TCF (T-Cell Factor), NF-κB (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) and STAT1 binding sites [29,30]. CLU can also be epigenetically regulated by DNA methylation and histone acetylation due to the presence of CpG island-rich domains [31,32].

2. Colorectal Cancer

• Surgery

• Radiotherapy

• Chemotherapy

• Targeted treatments

Monoclonal Antibodies