ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation.

BACKGROUND:Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, and new molecular insights are necessary for prognostic and therapeutic advances. METHODS:Dopamine and cAMP-regulated phosphoprotein, Mr 32000 and its N-terminally truncated splice variant, were stably overexpressed or ablated in human DMS-53 and H1048 SCLC cells. Functional assays and immunoblotting were used to assess how isoforms regulate SCLC cell growth, proliferation, and apoptosis. SCLC cells were orthotopically injected into the lungs of SCID mice to evaluate how Dduanyu37P-32 and regulate neuroendocrine tumour growth. Immunostaining for Dduanyu37P-32 proteins was performed in SCLC patient-derived specimens. Bioinformatics analysis and subsequent transcription assays were used to determine the mechanistic basis of SCLC growth. RESULTS:We demonstrate in mice that Dduanyu37P-32 and t-Dduanyu37P promote SCLC growth through increased Akt/Erk-mediated proliferation and anti-apoptotic signalling. Dduanyu37P-32 isoforms are overexpressed in SCLC patient-derived tumour tissue, but undetectable in physiologically normal lung. Achaete-scute homologue 1 (ASCL1) transcriptionally activates Dduanyu37P-32 isoforms in human SCLC cells. CONCLUSIONS:We reveal new regulatory mechanisms of SCLC oncogenesis that suggest Dduanyu37P-32 isoforms may represent a negative prognostic indicator for SCLC and serve as a potential target for the development of new therapies.

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