CARMA3 shRNA induces cisplatin sensitivity in ovarian cancer cells


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Jiyuan Sun1,Ganesh Panta2
1The University of Texas MD Anderson Cancer Center, Houston, Texas, United States,2IDEXX Labs, Westbrook, Maine, United States

Background

Ovarian cancer is ranked as the 4th most common type of cancer among women in the United States. The standard chemotherapy for ovarian cancer typically includes cisplatinum. It has been reported that inhibition of NF-kappaB increases the efficacy and chemosensitivity of cisplatin in vitro and in vivo in ovarian cancer models. The activation of NF-kappaB is mostly induced by lysophosphatidic acid (LPA), which is significantly elevated in 90% of ovarian cancer patients, thereby leading to cisplatinum-resistance. In our previous studies, we have demonstrated that CARMA3 plays an indispensable role in LPA or G protein-coupled receptor-induced NF-kappaB activation. In the present study, we further investigated whether knockdown of CARMA3 will sensitizes cisplatin-resistant ovarian cancer cells through inhibition of LPA-induced NF-kappaB-mediated cell survival signaling.

Method

Using CARMA3 shRNA, we silenced the expression of CARMA3 in ovarian cancer cells and detected the LPA-induced IKK activity and NF-kappaB activation. In addition, we evaluated the proliferation ability of ovarian cancer cells and the expression of apoptosis genes.

Results

Using CARMA3 shRNA, we demonstrated that down-regulation of CARMA3 abolished LPA-induced IKK activity and NF-kappaB activation in ovarian cancer cells. In addition, down-regulation of CARMA3 significantly enhanced cisplatin-induced apoptosis and inhibited cell proliferation in cisplatin-resistant ovarian cancer cells. Mechanistically, the enhanced chemosensitivity was mediated by down-regulation of NF-?B-regulated anti-apoptotic genes. Our results have shown that knockdown of CARMA3 sensitizes cisplatin-resistant ovarian cancer cells through inhibition of LPA-induced and NF-kappaB mediated cell survival signaling.

Conclusion

Together, our results suggest that CARMA3 may be a therapeutic drug target to enhance chemosensitivity in cisplatin-resistant ovarian cancer cells.