Mutant p53 potentiates the oncogenic effects of insulin by inhibiting the tumor suppressor DAB2IP

Abstract

Obesity and type 2 diabetes are significant risk factors for malignancies, being associated with chronic inflammation and hyperinsulinemia. In this context, insulin can synergize with inflammation to promote proliferation, survival, and dissemination of cancer cells. Point mutation of p53 is a frequent event and a significant factor in cancer development and progression. Mutant p53 protein(s) (mutp53) can acquire oncogenic properties that increase metastasis, proliferation, and cell survival. We report that breast and prostate cancer cells with mutant p53 respond to insulin stimulation by increasing cell proliferation and invasivity, and that such a response depends on the presence of mutp53. Mechanistically, we find that mutp53 augments insulin-induced AKT1 activation by binding and inhibiting the tumor suppressor DAB2IP (DAB2-interacting protein) in the cytoplasm. This molecular axis reveals a specific gain of function for mutant p53 in the response to insulin stimulation, offering an additional perspective to understand the relationship between hyperinsulinemia and cancer evolution.

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

“…Notably, mutant p53 can activate TNFα-induced NF-κB pathway through the transcriptional inhibition of the tumor suppressor DAB2IP, a cytoplasmic inhibitor of NF-κB and concomitantly hampering TNFα-induced activation of ASK1/JNK [162,163]. This dual effect orchestrated by mutant p53 increases the secretion of chemokines resulting in lymphocytes infiltration and severe inflammatory tumor microenvironment.…”

CDCA3 is a potential prognostic marker that promotes cell proliferation in gastric cancer

“…Previous studies have demonstrated that the RAS-GTP enzyme-activated protein DAB2IP can combine with DAB2 to produce a specific protein complex, which can exert a negative regulatory effect on the ERK/MAPK signaling pathway (23)(24)(25). Research has been performed in recent years demonstrating that there is a low expression of DAB2IP in numerous malignant tumors, including prostate and breast cancer (26,27). Furthermore, additional studies have demonstrated that the downregulation of endogenous DAB2IP expression can enhance the proliferation of prostate and breast cancer (28,29).…”

Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells

“…Although we have not investigated this aspect, it is possible that DAB2IP inhibition is part of the mechanisms through which these miRNAs promote proliferation, survival, and motility of cancer cells. For instance, miR-96 and miR-92a were reported to activate PI3K/AKT/mTOR signaling [20,42], a phenotype potentially enhanced by DAB2IP loss [9].…”

“…Transwell migration and invasion assays were performed as described previously [8,9]. In experiments with conditioned medium, cells were pre-incubated with Ctrl or PC3conditioned medium for 24 h, and subsequently seeded in the presence of Ctrl or PC3-conditioned medium; the lower chamber of the transwell system was filled with high-serum medium.…”

“…Multiple E3 ubiquitin-ligases can promote its turnover, while AKT kinase-mediated phosphorylation counteracts DAB2IP functions [4,5]. In addition, cytoplasmic interaction with tumorassociated p53 mutants blocks DAB2IP inhibitory activity on NF-κB and on AKT, favoring respectively cancer cell dissemination in response to inflammatory stimuli [8], and insulin-induced proliferation and invasion of tumor cells [9]. Finally, due to the rather long 3′UTR sequence of its main transcripts, DAB2IP is a strong candidate for posttranscriptional regulation by microRNAs (miRNAs).…”