Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Pro-inflammatory PGE₂, and elevated IGF-1 related to insulin resistance, are both shown to play critical roles in pancreatic cancer progression. We aimed at exploring a potential crosstalk between the PGE₂ signaling and IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE₂ stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently using pharmacological and genetic approaches, we demonstrated that PGE₂-induced mTORC1 activation is mediated by EP4/cAMP/PKA, as well as an EP1/Ca²⁺-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the co-existence of highly expressed EP1 (mediating Ca²⁺ response) and EP2 or 4 (mediating cAMP/PKA pathway) in PANC-1 and a prostate cancer line PC-3, which also robustly exhibited PGE₂-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE₂ and IGF-1 on mTORC1 signaling, with an increased IL-23 production as a cellular outcome. Together, our data reveal a previously unrecognized mechanism of PGE₂-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca²⁺ signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.