Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling

Abstract

The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.

Coniferaldehyde ameliorates the lipid and glucose metabolism in palmitic acid‐induced HepG2 cells via the LKB1/AMPK signaling pathway

“…LKB1 represents the primary AMPK upstream kinase and its phosphorylation at Ser428 is essential for LKB1‐induced AMPK activation (Gowans et al., 2013; Li et al., 2019). CaMKKβ is activated in response to an increase in intracellular Ca 2+ (Day et al., 2017).…”

Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

“…TNKS1/2 catalytic activity does not only regulate the stability of AXIN proteins, but also interferes with additional biological mechanisms and cell signaling pathways including telomere homeostasis, mitotic spindle formation, vesicle transport, and energy metabolism, as well as AKT/PI3K, AMPK and Hippo signaling 19,[24][25][26] . In Hippo signaling, tankyrase inhibitormediated stabilization of angiomotin (AMOT) proteins shifts the subcellular location of the transcription cofactors yes associated protein 1 (YAP) and tafazzin (TAZ), leading to a reduction of oncogenic YAP signaling 27,28 .…”

Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice

“…Similar to these observations, both global deficiency and adipocyte-selective inactivation of TNKS1 lead to reduced fat mass [17,18]. A recent publication by Li et al showed improved glycemic control after administering 30 mg G007-LK/kg/day for 30 days, five times a week [43]. In contrast, in our study the inhibitor treatment (14 mg G007-LK/kg/day) did not reduce blood glucose, suggesting that a high dose of G007-LK may be required for achieving better glycemic control in db/db mice.…”

“…On the other hand, it has been shown in vitro in L6 myocytes, that TNKS inhibition results in reduced insulin stimulated glucose uptake [44]. If TNKS inhibition would increase insulin resistance in a similar manner in vivo, this could counteract the positive effect of weight loss on insulin sensitivity, though this contradicts with the study by Li et al [43]. The effects of TNKS inhibition on glucose uptake appear to be cell-type specific, as TNKS inhibition has been shown to enhance glucose uptake into adipocytes [45].…”