Abstract
Basal cell carcinoma (BCC) is a locally invasive epithelial cancer that is primarily driven by the Hedgehog (HH) pathway. Advanced BCCs are a critical subset of BCCs that frequently acquire resistance to Smoothened (SMO) inhibitors and identifying pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify a PI3K pathway expression signature in BCC. Pharmacological inhibition of PI3K activity in BCC cells significantly reduces cell proliferation and HH signaling. However, treatment of Ptch1fl/fl; Gli1-CreERT2 mouse BCCs with the PI3K inhibitor BKM120 results in a reduction of tumor cell growth with no significant effect on HH signaling. Downstream PI3K components aPKC and Akt1 showed a reduction in active protein, whereas their substrate, cyclin-dependent kinase inhibitor p21, showed a concomitant increase in protein stability. Our results suggest that PI3K promotes BCC tumor growth by kinase-induced p21 degradation without altering HH signaling.
Highlights
The Hedgehog (HH) pathway is an evolutionarily conserved signaling pathway that plays an essential role in vertebrate embryogenesis and adult tissue homeostasis [1]
phosphoinositide 3-kinase (PI3K)/AKT Pathway Is Upregulated in Advanced basal cell carcinoma (BCC) Tumors
Differential gene expression analysis across the 14 tumor-normal pairs identified 1602 genes that were upregulated by two-fold or more in the resistant BCC tumors compared to their normal skin counterparts [48]
Summary
The Hedgehog (HH) pathway is an evolutionarily conserved signaling pathway that plays an essential role in vertebrate embryogenesis and adult tissue homeostasis [1]. In the normal vertebrate cell state, ion-driven cholesterol transporter Patched (PTCH1) actively depletes cholesterol from the membrane of the primary cilium and inhibits the cholesterol-dependent activation of SMO [15] This inhibition allows Suppressor of Fused homolog (SUFU) to sequester the Glioma-associated oncogene (GLI) transcription factors [16] and facilitate their post-translational proteolytic processing into repressor forms [17]. The PI3K pathway functions in therapeutic resistance against SMO inhibitors in medulloblastoma [36] and esophageal adenocarcinoma [37] Combinatory inhibition of both PI3K and HH signaling pathways in preclinical studies on medulloblastoma have demonstrated favorable efficacy in attenuating SMO inhibitorresistant tumors [36], the effects on other HH-mediated cancers like BCC remains to be determined. Our results suggest that the PI3K pathway functions in parallel to or downstream of the HH pathway to promote BCC tumor growth
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