Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells.

Yaming Ding,Tafail Akbar Mughal,Linlin Liu,Muhammad Zubair Saleem,Zhang Zhen,Muhammad Khan,Farman Ali,Muhammad Azhar Nisar,Riaz Ud Din,Gulzar Alam

doi:10.3389/fphar.2022.795613

Abstract

Paclitaxel resistance is a challenging factor in chemotherapy resulting in poor prognosis and cancer recurrence. Signal transducer and activator of transcription factor 3 (STAT3), a key transcription factor, performs a critical role in cancer development, cell survival and chemoresistance, while its inactivation overwhelms drug resistance in numerous cancer types including lung cancer. Additionally, the fucosyltransferase 4 (FUT4) is a crucial enzyme in post-translational modification of cell-surface proteins involved in various pathological conditions such as tumor multidrug resistance (MDR). The P-glycoprotein (P-GP) is the well-known ABC transporter member that imparts drug resistance in different cancer types, most notably paclitaxel resistance in lung cancer cells. LncRNA-MALAT1 exerts a functional role in the cancer development as well as the drug resistance and is linked with STAT3 activation and activity of FUT4. Moreover, STAT3-mediated induction of P-GP is well-documented. Natural compounds of Sesquiterpene Lactone (SL) family are well-known for their anticancer properties with particular emphasis over STAT3 inhibitory capabilities. In this study, we explored the positive correlation of MALAT1 with STAT3 and FUT4 activity in paclitaxel resistant A549 (A549/T) lung cancer cells. Additionally, we investigated the anticancer activity of two well-known members of SLs, alantolactone (ALT) and Brevilin A (Brv-A), in A549/T lung cancer cells. ALT and Brv-A induced apoptosis in A549/T cells. Furthermore, these two natural SLs suppressed MALAT1 expression, STAT3 activation, and FUT4 and P-GP expression which are the hallmarks for paclitaxel resistance in A549 lung cancer cells. The inhibition of MALAT1 enhanced the competence of these SLs members significantly, which accounted for the growth inhibition as well as anti-migratory and anti-invasive effects of ALT and Brv-A. These findings suggest SLs to be the promising agents for overcoming paclitaxel resistance in A549 lung cancer cells.

Highlights

Among different types of cancer, the most lethal type is the lung cancer worldwide having highest mortality, morbidity, and metastatic rate
After establishing the expected role of MALAT1, STAT3, and fucosyltransferase 4 (FUT4) in resistant and non-resistant lung cancer cells, we further studied the association of MALAT1 with STAT3 and FUT4
We assessed the expression of STAT3 and FUT4 in A549/T cells transfected with siRNA-MALAT1

Summary

Introduction

Among different types of cancer, the most lethal type is the lung cancer worldwide having highest mortality, morbidity, and metastatic rate. The side effects and drug tolerance in chemotherapy at the advanced stage are overwhelming factors. Due to the drug tolerance, patients within advanced stage of tumor have less response to the chemotherapy (Scheff and Schneider, 2013; Zhou et al, 2019). Paclitaxel is widely used in cancer treatment, primarily as a first-line chemotherapeutic drug against clinical manifestations of NSCLC (Pilkington et al, 2015; Yuan H. et al, 2016; Chen et al, 2017). Paclitaxel has improved the curative rates in both earlier and advanced stages of the disease and enhanced furtherance in the quality and life span of NSCLC patients (Zeng et al, 2015), paclitaxel resistance is a challenging obstacle to the successful treatment that creates a hiatus in the multimodal chemotherapeutic approach (Suda and Mitsudomi, 2015; Li et al, 2019)

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