A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties

Abstract

The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism and cell polarity. We now report the identification of a novel isoform of LKB1 (named ΔN-LKB1) that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The ΔN-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although ΔN-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory autoinhibitory domain of AMPK. In contrast, ΔN-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showed that ΔN-LKB1 has an intrinsic oncogenic property. ΔN-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of ΔN-LKB1 decreased the survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both the LKB1 tumor suppressor gene and the oncogene ΔN-LKB1 are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.

Different prognostic impact ofSTK11mutations in non-squamous non-small-cell lung cancer

“…Strikingly, the top enriched signature was described to be associated with prognosis and recurrence in breast cancers [16]. In their original work, the authors demonstrated that silencing ΔN isoform using a ΔN-STK11 shRNA reduced tumor growth in a xenograft model with H460 lung cancer cell line that carries an exon1 mutation and expresses solely the ΔN isoform [12]. These data suggest that the inhibition of ΔN-STK11 in lung cancer with STK11 ex1-2 mutations could be a potential therapeutic option.…”

“…In lung cancer, a short STK11 isoform lacking the 124 N-terminal amino acids has recently been described as an oncogene [12]. This ΔN isoform is produced from internal translation using an alternative ATG initiation codon located in exon 3 in the context of a mutation occurring in exon 1 or 2 and lacks the nuclear localization signal and part of the kinase domain.…”

A Sensitive NanoString-Based Assay to Score STK11 (LKB1) Pathway Disruption in Lung Adenocarcinoma

“…Previous work has identified three alternatively spliced isoforms of STK11 ; 1) the full-length 50-kDa isoform, 2) a 48-kDa isoform with an alternative C-terminus that is expressed in the testis 39 and 3) an oncogenic, but kinase inactive, 42-kDa isoform that is mainly expressed in normal heart and skeletal muscle 40 that is reported to be expressed (along with other shortened STK11 isoforms) at high levels in tumors with mutations in STK11 codons 1 and 2 41 . Such isoforms could potentially obscure standard IHC assessment of STK11 pathway status.…”

Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells (Review)

“…It is well known that LKB1 controls cell polarity and maintains intracellular energy balance (8,9). LKB1 functions as a tumor suppressor by phosphorylating and activating AMP-activated protein kinase (AMPK) (8,9).…”

“…LKB1 functions as a tumor suppressor by phosphorylating and activating AMP-activated protein kinase (AMPK) (8,9). LKB1/AMPK signaling regulates the formation of cytoskeletal microtubules and the expression of cell polarity proteins, including prostate apoptosis response-4 (PAR-4), to maintain cell polarity (10).…”