Overexpression of ARHI increases the sensitivity of cervical cancer cells to paclitaxel through inducing apoptosis and autophagy.

Abstract

Cervical cancer (CC) is a common malignant tumor of the female reproductive system. This study investigated the role of aplysia ras homolog I (ARHI) in resistance to CC in vitro and in patients' tissues. Hela cells were continuously treated with different concentrations of paclitaxel (1-10nM) to construct paclitaxel-resistant cell model (Hela-TR). CC or CC-TR tissues were obtained from CC patients or CC patients who had developed paclitaxel resistance. The level of ARHI and multidrug resistance gene 1 (MDR1) in cells and tissues were detected by qRT-PCR and immunohistochemistry (IHC) staining. Cell viability, apoptosis and the number of colonies were assessed by MTT, flow cytometry and cell clone assay in Hela and Hela-TR cells after the ARHI plasmid or shARHI were transfected into cells. The autophagy and apoptosis signaling related proteins were analyzed by western blotting. The results revealed that the levels of ARHI mRNA and protein were down-regulated in CC tissues, and were further reduced in paclitaxel-resistant tissues and Hela cell model. High expression of ARHI inhibited the expression of MDR1 in Hela and Hela-TR cells. The cell viability and cell clone of Hela and Hela-TR cells were decreased by ARHI overexpression but increased by ARHI suppression. In addition, highly expressed ARHI promoted apoptosis and activated autophagy by increasing LC3-II/LC3-I through inactivating AKT/mTOR signaling pathway. In conclusion, overexpression of ARHI can increase the sensitivity of CC to paclitaxel through promoting apoptosis and autophagy in a AKT/mTOR inactivation dependent pathway.