Zeta-crystallin: a moonlighting player in cancer

Abstract

Crystallins were firstly found as structural proteins of the eye lens. To this family belong proteins, such as ζ-crystallin, expressed ubiquitously, and endowed with enzyme activity. ζ-crystallin is a moonlighting protein endowed with two main different functions: (1) mRNA binding with stabilizing activity; (2) NADPH:quinone oxidoreductase. ζ-crystallin has been clearly demonstrated to stabilize mRNAs encoding proteins involved in renal glutamine catabolism during metabolic acidosis resulting in ammoniagenesis and bicarbonate ion production that concur to compensate such condition. ζ-crystallin binds also mRNAs encoding for antiapoptotic proteins, such as Bcl-2 in leukemia cells. On the other hand, the physiological role of its enzymatic activity is still elusive. Gathering research evidences and data mined from public databases, we provide a framework where all the known ζ-crystallin properties are called into question, making it a hypothetical pivotal player in cancer, allowing cells to hijack or subjugate the acidity response mechanism to increase their ability to resist oxidative stress and apoptosis, while fueling their glutamine addicted metabolism.

Keywords: Ammoniagenesis in cancer; Apoptosis; Cancer metabolism; Metabolic acidosis; RNA metabolism.

Fig. 1

Overview of CryZ expression at RNA level in various human tissues [96]. Color coding is based on tissue groups, each consisting of tissues with functional features in common. Data are relative to CryZ mRNA expression levels in different human normal tissues and arise from Human Protein Atlas (HPA) dataset [97]. Data are reported as mean transcript per million (TPM), corresponding to mean values of the different individual samples from each tissue. Specimens were collected with the consent from patients and all samples were anonymized in accordance with approval from the local ethics committee (ref #2011/473) and Swedish rules and legislation. All tissues (for a total of 172 tissue samples) were collected from the Uppsala Biobank and RNA samples were extracted from frozen tissue sections

Fig. 2

Overview of CryZ mRNA expression in 17 human cancer types. Color coding is based on the normal organ (the same as in Fig. 1) the cancer originates from. Data arising from RNA-seq analyses are reported as median FPKM (number of Fragments Per Kilobases of exon per Million reads) and are generated by The Cancer Genome Atlas (TCGA) [97]. Normal distribution across each dataset is visualized with box and whiskers plots: box is shown as median and 25th and 75th percentiles; whiskers are plotted following calculation by Tukey method

Fig. 3

The proposed CryZ integrated circuitry in cancer cells. Extracellular acidosis is a hallmark of cancer metabolism. Extracellular pH can be sensed by specific membrane receptors. The receptor-coupled intracellular signaling is translated into CryZ activity modifications impacting on apoptosis resistance and glutaminolysis increase. Gene transactivation and quinone detoxification could be also triggered. Inactivating mutations of p53 avoids CryZ gene transrepression, thus possibly strengthening CryZ activities by protein accumulation