Small Cell Lung Cancer Establishes a Metabolic Autocrine Mechanism Through Active Extracellular ATP Transport.

Small cell lung cancer (SCLC) is an aggressive malignancy with a 5-year survival rate of less than 7%. SCLC is characterized by accelerated de novo purine nucleotide biosynthesis, which fuels its rapid proliferation. While ATP serves as an essential metabolic substrate for nucleotide polymer synthesis and as the universal energy currency that fuels essential biological processes, it can also act as a potent extracellular signaling molecule. Here, we identify an autocrine mechanism in which SCLC actively exports ATP to the extracellular space through pannexin 1 (PANX1) channels, thereby promoting its own proliferation via purinergic signaling. Marked elevation of extracellular ATP was observed in SCLC cells. Clinical meta-analysis revealed that high PANX1 expression is significantly associated with poor survival in SCLC patients. Pharmacological inhibition or genetic knockdown of PANX1 suppressed extracellular ATP levels and markedly reduced SCLC cell proliferation, whereas PANX1 overexpression increased extracellular ATP and accelerated growth. This ATP efflux is driven by calcium-dependent activation of PANX1, with the calcium/calmodulin-dependent protein kinase II (CaMKII)-TRPA1 axis identified as a key upstream regulator. Moreover, blockade of the P2RX7 receptor abrogated ATP-induced proliferation, indicating that SCLC establishes a metabolic autocrine loop through ATP release and P2RX7 activation. In mouse xenograft models, PANX1 knockdown suppressed, whereas PANX1 overexpression enhanced, tumor growth in vivo. These findings indicate that SCLC exploits a PANX1-dependent ATP release mechanism to engage P2RX7-mediated autocrine signaling and suggest that targeting this axis may represent a potential therapeutic opportunity for this lethal cancer.