AMPK Activators Suppress Cervical Cancer Cell Growth through Inhibition of DVL3 Mediated Wnt/β-Catenin Signaling Activity

Abstract

Recent evidence has suggested that AMPK activators may be applied as therapeutic drugs in suppressing cancer cell growth. However, the molecular mechanism of their suppressive function in cancer cells is still unclear. Here we show that AMPK activators impair cervical cancer cell growth through the reduction of DVL3, a positive regulator in Wnt/β-catenin signaling and an oncogenic player in cervical cancer tumorigenesis. By western blot and immunohistochemical analyses, we demonstrated that DVL3 was frequently upregulated and significantly associated with elevated β-catenin (P = 0.009) and CyclinD1 (P = 0.009) expressions in cervical cancer. Enforced expression of DVL3 elevated β-catenin and augmented cervical cancer cell growth, verifying that DVL3-mediated Wnt/β-catenin activation is involved in cervical cancer oncogenesis. On the other aspect, we noted that the cervical cancer cell growth was remarkably suppressed by AMPK activators and such cell growth inhibition was in concomitant with the reduction of DVL3 protein level in dose- and time-dependent manners. Besides, impaired mTOR signaling activity also reduced DVL3 expression. In contrast, co-treatment with Compound C (AMPK inhibitor) could significantly abrogate metformin induced DVL3 reduction. In addition, co-treatment with AM114 or MG132 (proteosomal inhibitors) could partially restore DVL3 expression under the treatment of metformin. Further in vivo ubiquitination assay revealed that metformin could reduce DVL3 by ubiquitin/proteasomal degradation. To our knowledge, this is the first report showing the probable molecular mechanisms of that the AMPK activators suppress cervical cancer cell growth by impairing DVL3 protein synthesis via AMPK/mTOR signaling and/or partially promoting the proteasomal degradation of DVL3.

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

“…Indeed, previous studies reported by our team showed that pharmaceutical AMPK activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) (ATP-dependent) and A23187 (ATP-independent) could be used to suppress cervical cancer cell growth harboring with or without LKB1, an upstream kinase of AMPK [44]. Our group also proposed mechanistic evidence showing that metformin, AICAR, and A23187 suppress cell growth of cervical cancer through reducing AKT/FOXO3a/FOXM1 signaling [47] and DVL3, a positive effector of Wnt/β-catenin signaling cascade, has been shown to be activated constitutively in cervical cancer development [48]. More importantly, our latest study of the molecular mechanism revealed that BME acts as a natural AMPK activator through CaMKKβ signaling in an AMP-independent manner, which in turn represses both mTOR/p70S6K and AKT/ERK/FOXM1 signals in ovarian cancer cells (Fig.…”

Metformin use and survival after colorectal cancer: A population‐based cohort study

“…4 Increasing lag to 1 year among individuals living more than 1 year after cancer diagnosis. 5 Increasing lag to 2 year among individuals living more than 2 years after cancer diagnosis. 6 Adjusted model contains all variables in " 1" along with BMI prior to diagnosis (in individuals with BMI available).…”

“…1 Preclinical evidence suggests a beneficial role for metformin, a first-line oral anti-diabetic agent, in colorectal cancer progression. [2][3][4] Although not fully elucidated, the potential anti-tumour effects of metformin are thought to be due to inhibition of the mammalian target of rapamycin (mTOR) signalling pathway, resulting in suppression of cellular proliferation 5 tumour cell migration and invasion 6 as well as an increase in apoptosis. 7 Despite mounting preclinical evidence supporting a possible therapeutic role for metformin in colorectal cancer, only two epidemiological studies have evaluated the impact of post-diagnostic metformin exposure on cancer outcomes in colorectal cancer patients with type 2 diabetes.…”

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

“…Aspirin is also reported to induce the mitochondria/ caspase-3 apoptotic pathway, which is dependent on the Wnt/b-catenin signaling in mesenchymal stem cells (93). For metformin, it has been reported to inhibit the activation of Wnt/b-catenin signaling in cervical cancer cells (94). Metformin has also been reported to increase the expression of Bambi, a TGF-b decoy receptor, and induce prosurvival Wnt/b-catenin signaling in hepatic stellate cells (95).…”