Cisplatin chemoresistance increases stemness proprieties of human non-small cell lung cancer

ANDRES BECHIS; AGUSTINA TARUSELLI; LIZETH ARIZA BAREÑO; MARIA J. COSTA; DAMIAN DELBART; ALEJANDRO J. URTREGER; LAURA B. TODARO

Mar del Plata

Congreso; LXIV Reunión Científica de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

Sociedad Argentina de Investigación Clínica (SAIC)

Non-small cell lung cancer (NSCLC) is the most frequent lung malignancy in the world. Currently, cisplatin is the standard therapy for this disease, although there is a frequent acquisition of resistance. The presence of cancer stem cells (CSC) is associated with the above-mentioned resistance, and the Retinoic Acid System, among other systems, has been implicated in the maintenance and expansion of CSC.In order to evaluate the involvement of retinoic acid (ATRA) in growth modulation in a chemoresistance context, we have developed a cisplatin-resistant variant from NSCLC A549 cell line (A549cpr).Monolayers of parental and cisplatin-resistant A549 cells were treated with ATRA (0.3 - 70 uM) and/or Cisplatin for 72 h. While the Cisplatin treatment IC50 (6.87+1.04 uM and 18.08+1.03 uM for A549 and A549cpr respectively) induce growth inhibition, ATRA addition did not modify proliferative capacity. Although both cell lines express all nuclear Retinoic Acid Receptors, A549cpr cells showed lower levels of the RARβ isotype, involved in differentiation (determined by RT-qPCR). Moreover, ATRA treatment (1 uM) increased RARβ levels in both A549 variants, indicating that retinoic system is active.Finally, we studied the CSC component of A549 and A549cpr cells through an oncosphere culture. Although no differences were observed in oncosphere formation capacity, A549cpr cells present larger oncosphere colonies. This phenomenon was accompanied with higher Nanog mRNA expression levels, involved in cell pluripotentiality. In all cases, Nanog expression was higher in oncospheres than in the respective monolayers.Our results reinforce the hypothesis that cisplatin resistance may be mediated by an increase in CSC renewal. These findings lead us to propose different combination therapies for targeting CSC.