p38 kinase is a negative regulator of tumorigenesis and recurrence after surgery in a mammary carcinoma model.

CAPOBIANCO, CARLA SABRINA; SIDABRA, JOHANNA ELENA; GOTTARDO, MARÍA FLORENCIA; AGUIRRE-GHISO, JULIO A; ALONSO, DANIEL; FARINA, HERNAN GABRIEL

Chicago

Congreso; AACR Annual Meeting 2018; 2018

The mitogen activated protein kinase (MAPK) p38 is a kinase involved in the response to different external stimuli, extremely diverse such as oxidative stress or growth factors. Its activation triggers different responses which include from promoting cell apoptosis or cell cycle arrest, to cell differentiation and the activation of survival pathways. Although the role of p38 in cancer is a well studied field, there are still multiple unanswered questions, given the large amount of evidence supporting both a tumorigenic but also a tumor suppressor function for p38 in cancer development and progression. In this study, the effects produced by p38 negative modulation using the chemical inhibitor SB203580 in different aspects of tumor biology are analyzed in vitro and in vivo. As a study model, F3II cell line was used, which is an aggressive murine mammary carcinoma. We found that p38 inhibition provokes contradictory effects in our mammary carcinoma model. On one hand, p38 inhibition provoked the reduction of cell viability and colony formation. On the other hand, SB203580 treatment increased cell adhesion and proliferation in matrix coated surfaces. In vivo we found that SB203580 treatment increases tumor aggressiveness. The shortened latency times, higher number of lung metastasis and larger local recurrences are a reflection of the aforementioned effect. Taking together, the results presented in this work position p38 as a tumor suppressor kinase, in the context of cells adapting to a new environment and developing the first stages of growth. P38 inhibition represented an advantage for cells newly inoculated in vivo. We consider that this phenotypic adaptation is probably a consequence of ERK activation and integrin α5 increased expression. Data presented here is of importance to show how determinant is the microenvironment in the responses elicited by the modulation of p38 kinase. We propose a differential role according to the environment conditions, which reflects the complexity of the pathway and the importance of the extracellular stimuli when evaluating the implications of treatment with p38 MAP kinase inhibitors.