Targeting PI3K‐IKKα‐CDK1 Signaling Pathway to Prevent Lung Cancer Progression and Resistance

Lung cancer is a deadly disease that affects the tissues in the lungs. It is the leading cause of cancer-related deaths worldwide, accounting for approximately 1.8 million deaths each year. The inhibitor of kappa B kinase alpha (IKKα) is a key component of NF-κB signaling with stimulatory functions in inflammation, proliferation, and metastasis, and also contributes to the development of treatment resistance. Hence, we examine the effects of IKKα silencing on the proliferation, sensitization of cells to doxorubicin, apoptosis and metastasis of A549 human lung cancer cell line and its downstream signal transduction. This study focused on investigating the effects of IKKα in the doxorubicin (DOX) mediated apoptosis with further detailed mechanisms in lung cancer. siRNA was used to silence IKKα. Cell viability was measured using an MTT assay. Western blot and qRT-PCR were used for the measurement of target proteins and mRNA expression levels. ELISA cell death assay was used to measure apoptosis. Simultaneous silencing of IKKα and treatment with DOX led to a dramatic elevation in the cytotoxic effects of DOX in A549 cells. In addition, siRNA against IKKα increased apoptosis and decreased metastasis in resistant cells. Moreover, si-IKKα downregulated the expression levels of CDK1/PI3K/AKT IKKα silencing led to the reversal of DOX resistance in A549 cells. IKKα silencing and DOX exposure elevated the DOX mediated cellular cytotoxicity by targeting the CDK1/PI3K/AKT axis, and apoptosis induction. These findings suggest that PI3K-IKKα-CDK1 may be a promising therapeutic strategy for human lung cancer treatment.