Investigation of SOX9 Mediated Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Reverting Potential of Piperlongumine in Lung Cancer

Tripathi, Surya Kant (2021) Investigation of SOX9 Mediated Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Reverting Potential of Piperlongumine in Lung Cancer. PhD thesis.

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SRY-related high mobility group box 9 (SOX9) has been identified as a promising transcription factor in the initiation and progression of various tumor types, including lung cancer. The present study investigates the role of SOX9 expression in EGFR-TKI (gefitinib) resistant lung cancer in vitro and ex vivo. It was found that upregulation of SOX9 was associated with gefitinib resistance with an increased rate of cell proliferation, migration and invasion, single-cell colony-forming ability, and reduced apoptosis in gefitinib resistant cells A549/GR and NCI-H522/GR. Moreover, upregulated SOX9 promoted epithelial to mesenchymal transition (EMT) via targeting β-catenin and its knockdown reversed the resistance and EMT phenotype in A549/GR and NCI-H522/GR cells. Similarly, it was found that multicellular spheroids of A549/GR and NCI-H522/GR cells showed a larger surface area with more dispersion, while SOX9 knockdown abolished these gained properties ex vivo. To date, many natural compounds have shown promising chemotherapeutic potential. Piperlongumine (PIP), a white to beige biologically active alkaloid has high pharmacological relevance as an anticancer agent. It has been found that PIP suppresses the cell proliferation, migration, and stem-cell-like phenotype by targeting SOX9, resulting in induction of apoptosis in A549 and NCI-H522 cells via attenuating EMT. PIP effectively showed cytotoxicity against A549 and NCI-H522 cells and induced reactive oxygen species (ROS) production and cell cycle arrest. Additionally, PIP induced dissipation in mitochondrial membrane potential and affected the expression of intrinsic apoptotic pathway proteins in lung cancer cells. PIP inhibited EMT and stemness of lung cancer cells. Further, ex vivo analysis revealed that PIP induced apoptosis and size reduction in multicellular spheroid of A549 and NCI-H522 cells. The emergence of resistance to gefitinib indicates that use of a single agent may not be sufficient for the effective treatment of lung cancer. Therefore, combinatorial effect of PIP with gefitinib in A549/GR and NCI-H522/GR cells was examined. The result suggested that co-treatment of PIP with gefitinib in lung cancer cells showed increased cytotoxicity as compared to gefitinib or PIP alone and reversed the resistance via inhibiting EMT. At last, the overall study delineated a deep insight into the mechanism of PIP mediated cancer inhibition and its combinatorial therapeutic effect in re-sensitization of SOX9 induced EGFR-TKI resistance in lung cancer.

Item Type:Thesis (PhD)
Uncontrolled Keywords:Lung cancer; SOX9; EGFR-TKI; Gefitinib resistance; Piperlongumine; EMT; Combination therapy
Subjects:Life Science > Molecular Meidicine
Life Science > Cancer Biology
Life Science > Microbiology
Divisions: Sciences > Department of Life Science
ID Code:10349
Deposited By:IR Staff BPCL
Deposited On:14 Dec 2022 14:04
Last Modified:14 Dec 2022 14:04
Supervisor(s):Biswal, Bijesh Kumar

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