Cross-talk between Endoplasmic Reticulum (ER) Stress and the MEK/ERK Pathway Potentiates Apoptosis in Human Triple Negative Breast Carcinoma Cells

• Published in: The Journal of biological chemistry 2015-02, Vol.290 (7), p.3936-3949
• Main Authors: Ghosh, Swatilekha, Adhikary, Arghya, Chakraborty, Supriya, Bhattacharjee, Pushpak, Mazumder, Minakshi, Putatunda, Salil, Gorain, Mahadeo, Chakraborty, Arijit, Kundu, Gopal C., Das, Tanya, Sen, Parimal C.
• Format: Article
• Language: English
• Subjects: Apoptosis; Breast Cancer; Caspase; Endoplasmic Reticulum Stress (ER Stress); Extracellular Signal-regulated Kinase (ERK)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.594028

Triple negative breast cancers (TNBC) are among the most aggressive and therapy-resistant breast tumors and currently possess almost no molecular targets for therapeutic options in this horizon. In the present study we discerned the molecular mechanisms of potential interaction between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway in inducing apoptosis in TNBC cells. Here we observed that induction of ER stress alone was not sufficient to trigger significant apoptosis but simultaneous inhibition of the MEK/ERK pathway enhanced ER stress-induced apoptosis via a caspase-dependent mechanism. Our study also demonstrated nifetepimine, a dihydropyrimidone derivative as a potent anti-cancer agent in TNBC cells. Nifetepimine down-regulated the MEK/ERK pathway in MDAMB-231 and MDAMB-468 cells and resulted in blockage of ER stress-mediated GRP78 up-regulation. Detailed mechanistic studies also revealed that nifetepimine by down-regulating pERK expression also declined the promoter binding activity of TFII-I to the GRP78 promoter and in turn regulated GRP78 transcription. Studies further extended to in vivo Swiss albino and SCID mice models also revalidated the anti-carcinogenic property of nifetepimine. Thus our findings cumulatively suggest that nifetepimine couples two distinct signaling pathways to induce the apoptotic death cascade in TNBC cells and raises the possibility for the use of nifetepimine as a potent anti-cancer agent with strong immune-restoring properties for therapeutic intervention for this group of cancer bearers. Background: Triple negative breast cancers (TNBC) are resistant to conventional therapies and molecular targets of TNBC are not explored in detail. Results: Coupling of ER stress and the MEK/ERK pathway by nifetepimine effectively kills TNBC cells. Conclusion: Nifetepimine plays a significant role in inducing apoptosis in TNBC cells. Significance: Our findings strongly suggest that nifetepimine may act as a potent anti-cancer agent for treatment of TNBC.