Updated project metadata. Hyperinsulinemia, often associated with obesity and type 2 diabetes mellitus, is also linked to an elevated risk of various cancers. However, the specific mechanisms underlying this connection remain unclear. Here, we report that inhibiting neddylation, in the presence of insulin treatment, further promotes cancer cell migration in different cancer types by activating both insulin receptor substrate 1 and 2, as well as the PI3K/AKT signaling pathway. We also found that C-CBL neddylates IRS1 and IRS2 as an E3 ligase, with clinical evidence supporting its role as a tumor suppressor. Altogether, these findings suggest that the neddylation of IRS1 and IRS2 may be a bona fide suppressor of cancer cell migration. Thus, caution is advised when considering neddylation inhibitors as a treatment for cancer patients with obesity-related type 2 diabetes or hyperinsulinemic condition.