The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer

Abstract

Background The discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC. Methods Genetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models. Results PITPNC1 was increased in human LUAD and PDAC, and associated with poor patients’ survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC. Conclusions Our data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments.

Hairpin-Empowered Invasive Reaction Combined with Catalytic Hairpin Assembly Cascade Amplification for the Specific Detection of Single-Nucleotide Polymorphisms

“…Single-nucleotide polymorphism (SNP) mainly refers to the DNA sequence polymorphism caused by the variation of a single nucleotide at the genomic level, which may affect the structure and function of encoded proteins and also be closely related to a variety of human diseases, such as cancers, genetic diseases, and neuropsychiatric disorders. − Therefore, SNPs have been considered important biomarkers for early diagnosis and targeted therapy. , For example, the KRAS gene mutations that have been discovered are considered by researchers to be important biomarkers and therapeutic targets and are closely related to various high-incidence cancers including pancreatic, colon and lung cancers, so accurate and sensitive detection of SNPs of KRAS gene can provide an important reference for early diagnosis and risk assessment of KRAS gene-related cancers. − In addition, SNP is also an important basis for studying the genetic variation of plant strains. For example, the number of grains per pod of soybean, as an important yield trait, is controlled by a pair of alleles Ln/ln, which is a typical single SNP site strongly associated trait. , Therefore, an important way of modern molecular design breeding is to carry out fixed-point SNP detection for offspring individuals and directly track single or multiple SNPs linked with target traits, so as to reduce the blindness in the process of trait breeding and greatly improve the breeding efficiency.…”

Multi-omics analyses based on genes associated with oxidative stress and phospholipid metabolism revealed the intrinsic molecular characteristics of pancreatic cancer

“…Overall, oxidative stress, which compromises lipid function impairs and is related to lipid metabolic reprogramming, was found to function in the development and metastasis of cancer 7 , 19 , 20 . The disorders of phospholipid affect the development and drug sensitivity of PC 21 , 22 . The specific roles of OS and phospholipid metabolism (PM) in PC has not been investigated clearly.…”