Abstract
PUMA is a member of the “BH3-only” branch of the BCL-2 family. Our previous study suggests a therapeutic potential of PUMA in treating ovarian cancer, however, the action mechanism of PUMA remains elusive. In this work, we found that in PUMA adenovirus-infected A2780s ovarian cancer cells, exogenous PUMA was partially accumulated in the cytosol and mainly located to the mitochondria. We further showed that PUMA induces mitochondrial dysfunction-mediated apoptosis and ROS generation through functional BAX in a ROS generating enzyme- and caspase-independent manner irrespective of their p53 status, and results in activation of Nrf2/HO-1 pathway. Furthermore, PUMA induces DNA breaks in γ-H2AX staining, and causes activation of DNA damage-related kinases including ATM, ATR, DNA-PKcs, Chk1 and Chk2, which are correlated with the apoptosis. PUMA also results in ROS-triggered JNK activation. Intriguingly, JNK plays a dual role in both DNA damage response and apoptosis, and has an additional contribution to apoptosis. Taken together, we have provided new insight into the action mechanism by which elevated PUMA first induces ROS generation then results in DNA damage response and JNK activation, ultimately contributing to apoptosis in ovarian cancer cells.
Highlights
Ovarian cancer is one type of lethal gynecologic cancer [1, 2]
We have provided new insight into the action mechanism by which elevated PUMA first induces ROS generation results in DNA damage response and JNK activation, contributing to apoptosis in ovarian cancer cells
Our previous study showed that PUMA could chemosensitize ovarian cancer cells [2], the action mechanism remains elusive
Summary
Ovarian cancer is one type of lethal gynecologic cancer [1, 2]. Because ovarian cancer often has no symptom at the early stage, most of patients are diagnosed at the late stages [3]. Treatment with platinum and paclitaxel can prolong survival to some extent, drug resistance often leads to therapy failure [4, 5]. Some novel molecular targets have been discovered for treating ovarian cancer [6,7,8,9]. Recent reports suggest that deregulations in apoptotic pathways are associated with cancer progress [9, 10]. P53 mutation often causes resistance to chemotherapy [11, 12]. Previous studies showed that p73 is an important determinant for chemosensitivity [12,13,14]
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