Nicotine-Induced VEGF Levels in NSCLC Cells Are Modulated by PKA, Hyaluronan, and p53.

Nicotine promotes non-small cell lung cancer (NSCLC) survival in part by elevating vascular endothelial growth factor (VEGF), yet the upstream regulatory mechanisms remain unclear. Here we identify a PKA-HA-p53 regulatory axis that governs nicotine-driven VEGF levels and survival in A549 (p53(+)/(+)) and H1299 (p53-null) cells. Nicotine increased VEGF levels in the media, an effect augmented by protein kinase A (PKA) activation and reduced by PKA inhibition. Blocking hyaluronan (HA) synthesis with 4-methylumbelliferone (4-MU) lowered VEGF levels and diminished the nicotine response, suggesting that HA-CD44 contributes to PKA-linked survival pathways. In A549, p53 inhibition or knockdown enhanced PKA activity and VEGF levels, indicating that p53 constrains this axis; by contrast, H1299 displayed sustained nicotine responsiveness consistent with p53 loss. Pharmacologic nAChR/β-adrenergic blockade blunted nicotine-induced PKA signaling. Functionally, VEGF immunodepletion or co-treatment with a PKA inhibitor, 4-MU, or anti-VEGF antibodies reduced nicotine-supported viability and increased apoptosis, while the addition of purified VEGF rescued survival, establishing the role of VEGF in this pathway. Collectively, these findings delineate a mechanistic network in which PKA, HA-CD44 signaling, and p53 integrate nicotinic cues to control VEGF media levels and cell survival, identifying potential targets (PKA, HA synthesis, VEGF) for mitigating nicotine-mediated NSCLC progression.