Efekti inhibicije CXCR4 receptora i fokalne adhezione kinaze u supresiji invazije i prevazilaženju rezistencije kod nesitnoćelijskog karcinoma pluća
Effects of CXCR4 receptor and focal adhesion kinase inhibition in suppressing invasion and overcoming drug resistance in non-small cell lung carcinoma
Abstract:
Lung cancer is the most commonly diagnosed type of malignant tumor and the
leading cause of cancer death. Based on clinical prognosis and terapy response, up to
85% of lung cancer is clasified as non-small cell lung carcinoma (NSCLC). Although
NSCLC is less agresive than small cell lung carcinoma (SCLC), its response to terapy
is worse then SCLC. Two major causes of terapy failure of NSCLC with classic
chemotherapeutics are the development of metastasis and chemotherapy resistance.
Among other signaling molecules, CXCR4 receptor and focal adhesion kinase (FAK)
are known to regulate these processes and their targeted inhibition represents a
promising approach in the treatment of NSCLC. The aim of this study was to examine
the role of CXCR4 and FAK in the invasiveness and resistance of NSCLC, as well as
the potential of their inhibition in the suppression of invasion and the reversal of
resistance in this type of lung carcinoma. In order to examine the role of CXCR4 and
FAK in the invasiveness of NSCLC, in vitro system of cancer cell lines with different
functional status of the p53 and PTEN tumor suppressors was established, as well as
in vivo orthoptic metastatic model of NSCLC with p53/PTEN deficient tumors. The
simultaneous inactivation of p53 and PTEN tumor suppressors in in vitro system lead
to significant increase in invasive and migratory potential associated with activation
of CXCR4 and FAK molecules and their downstream signaling molecules, AKT and
ERK. The potential for supressing invasion and migration of p53-/PTEN- NSCLC
cells, as well as the metastatic spread of aggressive p53/PTEN deficient tumors in in
vivo model, has been shown by the application of specific inhibitors of CXCR4 and
FAK, PF-573228 and WZ811. Furthermore, resistant cell lines NCI-H460/R and
COR-L23 were used to investigate the role of CXCR4 and FAK in the development
of NSCLC resistance to chemotherapy. NCI-H460/R and COR-L23 cells are
characterized by an increased expression of ABCB1 and ABCC1 transporters,
respectively. Our results additionally indicate that inhibition of CXCR4 and FAK in
combination with DOX successfully sensitized NSCLC cells to the aforementioned
cytostatic. By examining the mechanism of sensitization of NSCLC cells to DOX, it
has been discovered that combined treatments reduced phosphorylation of FAK and
AKT and lead to activation of senescence. Simultaneously with sensitization of cells
to DOX, combined treatment successfully suppressed the invasion of resistant cells. Considering that resistance to therapy and metastasis are the two most
important problems in NSCLC treatment, the results of the study show that targeted
inhibition of CXCR4 and FAK, as well as their combination with standard
chemotherapeutics, could be a promising therapeutic approach in the treatment of this
disease.
Keywords:
CXCR4; FAK; p53; PTEN; Invasion; Doxorubicin; Resistance; ABCB1; BACC1; Non-small cell lung carcinomaSource:
University of Belgrade, Faculty of Biology, 2018, 1-145Funding / projects:
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
URI
http://uvidok.rcub.bg.ac.rs/handle/123456789/2946https://radar.ibiss.bg.ac.rs/handle/123456789/3157