Different toxic effects of YTX in tumor K-562 and lymphoblastoid cell lines

Abstract

Yessotoxin (YTX) modulates cellular phosphodiesterases (PDEs). In this regard, opposite effects had been described in the tumor model K-562 cell line and fresh human lymphocytes in terms of cell viability, cyclic adenosine 3',5'-cyclic monophosphate (cAMP) production and protein expression after YTX treatment. Studies in depth of the pathways activated by YTX in K-562 cell line, have demonstrated the activation of two different cell death types, apoptosis, and autophagy after 24 and 48 h of treatment, respectively. Furthermore, the key role of type 4A PDE (PDE4A) in both pathways activated by YTX was demonstrated. Therefore, taking into account the differences between cellular lines and fresh cells, a study of cell death pathways activated by YTX in a non-tumor cell line with mitotic activity, was performed. The cellular model used was the lymphoblastoid cell line that represents a non-tumor model with normal apoptotic and mitotic machinery. In this context, cell viability and cell proliferation, expression of proteins involved in cell death activated by YTX and mitochondrial mass, were studied after the incubation with the toxin. Opposite to the tumor model, no cell death activation was observed in lymphoblastoid cell line in the presence of YTX. In this sense, variations in apoptosis hallmarks were not detected in the lymphoblastoid cell line after YTX incubation, whereas this type I of programmed cell death was observed in K-562 cells. On the other hand, autophagy cell death was triggered in this cellular line, while other autophagic process is suggested in lymphoblastoid cells. These YTX effects are related to PDE4A in both cellular lines. In addition, while cell death is triggered in K-562 cells after YTX treatment, in lymphoblastoid cells the toxin stops cellular proliferation. These results point to YTX as a specific toxic compound of tumor cells, since in the non-tumor lymphoblastoid cell line, no cell death hallmarks are observed.

Yessotoxin, a Promising Therapeutic Tool

“…In the erythroleukemia K-562 cell line the apoptotic cell death was activated after 24 h YTX incubation when the AKAP 149-PKA-PDE4A complex was located in the plasma membrane [ 55 ]. In these cells, variations of both intrinsic (Bcl2 and caspases 3) and extrinsic (caspase 8) apoptotic hallmarks had been showed after 24 h of YTX incubation, indicating the activation of these two types of apoptotic cell death [ 55 , 65 ]. After YTX exposure, no external ligands to activate death-inducing signaling complex (DISC) were described [ 66 ].…”

“…The effect in cell viability was further studied in a lymphoblastoid cell line. This is a non-tumor model with normal apoptotic and mitotic machinery [ 65 ]. Again, opposite to tumor models, no cell death activation was observed in these cells after 24 or 48 h in the presence of YTX.…”

“…This line of reasoning based on AKAP 149 would explain the differences in response between normal and tumor cells to YTX. Indeed, surprisingly different molecular weights for PDE4A proteins were observed depending on the cellular model, 80 kDa in the case of K-562 cells, and 98 kDa, the normal molecular weight for this protein, in the lymphoblastoid cells [ 65 ]. In this sense, tumor cells have protein mutations that could lead to the change in the protein function, and these mutations are sometimes used as tumor biomarkers [ 80 ].…”

Yessotoxin, a Marine Toxin, Exhibits Anti-Allergic and Anti-Tumoural Activities Inhibiting Melanoma Tumour Growth in a Preclinical Model

“…Thus, previous studies in fresh human lymphocytes and K-562 lymphoma cells showed that they were, respectively, resistant and sensitive to YTX [14, 15]. Differential effects of YTX also showed that it does not induce cell death features in a lymphoblastoid cell line, whereas it induced apoptosis in the lymphocytic cell line K-562 [40]. …”

MTMR3 is upregulated in patients with breast cancer and regulates proliferation, cell cycle progression and autophagy in breast cancer cells

“…Conversely, MTMR3 caused a reduced autophagic activity and smaller nascent autophagosomes when overexpressed (19). LC3A and LC3B are widely used as autophagy biomarkers, and the type I (16 kDa) is converted to type II (14 kDa) (43). A significant upregulation in the LC3-II/LC3-I ratio was observed in the present study following MTMR3 knockdown, implying an activation of autophagy.…”