p38 kinase acts as a negative regulator of recurrence after surgery in a mammary carcinoma model, through apoptosis induction and proliferation inhibition.

CARLA S. CAPOBIANCO; MARIA F. GOTTARDO; JOHANNA E. SIDABRA; JULIO A. AGUIRRE GHISO ; DANIEL F. ALONSO; HERNAN G. FARINA

Filadelfia

Congreso; American Association for Cancer Research Annual meeting; 2020

American Association for Cancer Research

The p38 pathway can be activated by three different MAP kinase kinases: MKK3, MKK4 and MKK6, each one activated by different stimuli, like DNA damage, oxidative stress, proinflammatory cytokines or growth factors. In consequence, the responses mediated by this kinase are also significantly diverse. Its participation in such different processes makes it reasonable for the role of p38 in cancer to be a topic of current debate. Several authors reported a pro-tumorigenic role of p38, through the stimulation of tumor progression, epidermal to mesenchymal transition and migration and chemotherapy resistance, as a consequence of the transduction of pro-survival signals. Due to the above mentioned, the combination of p38 inhibitors and chemotherapy is frequently proposed as an interesting clinical approach for cancer treatment. In contrast, several reports underline the importance of p38 suppression of tumor initiation, metastasis inhibition through dormancy maintenance, and also a decisive role in the action mechanism of antitumor treatments under evaluation. Specifically, an important amount of evidence point p38 as a key apoptosis mediator in cancer cells, as a response to treatment with anticancer drugs included in different clinical and preclinical protocols. Previously we studied the effect of p38 inhibition in a mouse mammary carcinoma model named F3II. We described that in vitro inhibition of p38 provokes an increased in cell adhesion, cell spreading, proliferation in 3D cultures, ERK phosphorylation and Integrin α5 expression. In vivo inhibition also resulted in shortened latency times and increased tumor growth rates. In this work, we studied the effect of p38 inhibition in the development of recurrences after tumor surgery. When SB203580 inhibitor was administered after surgery, mice developed larger recurrences. Apoptotic cells in histological samples were detected by TUNEL analysis, showing that SB203580 treatment decreased the number of apoptotic cells in tumor recurrences. In addition, mitotic cell count in recurrence tissue showed that SB203580 treatment increased the mitotic index in the tumors. In conclusion, in this work we demonstrated that in F3II cell line, p38 inhibition promotes tumor recurrence development after surgery, mainly blocking the apoptotic response, and promoting cell duplication. Results presented in this work position p38 as a tumor suppressor kinase. The evidence presented here highlight the possible risk of the administration of a p38 inhibitor to oncological patients that may present newly disseminated cells, or a residual tumor mass that remains after treatment. From our perspective, candidates to be treated with new p38 inhibitors should be carefully selected according to the tumor type and the stage of the disease, since the response might be extremely variable between the different conditions.