Cryptotanshinone Activates p38/JNK and Inhibits Erk1/2 Leading to Caspase-Independent Cell Death in Tumor Cells

Abstract

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal–regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-l-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells.

Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling

“…28 It has been found that CPT leads to caspaseindependent cell death in Rh30 and DU145 cells by activating p38/JNK signaling and inhibiting Erk1/2 signaling in a reactive oxygen species (ROS) dependent manner. 22 CPT has been found to induce MCF7 cell apoptosis in a similar manner. Additionally, recent studies demonstrated that CPT induces endoplasmic reticulum (ER) stress-mediated apoptosis in MCF7 cell via ROS generation.…”

“…[14][15][16][17] Recently, CPT has also been reported to have obvious antitumor activity in a variety of cancer cells, including prostate carcinoma, hepatocarcinoma, rhabdomyosarcoma and melanoma cells. [18][19][20][21][22][23] In breast carcinoma cells, CPT has been shown to inhibit MCF7 cell proliferation by suppressing mTOR mediated CyclinD1 expression and Rb phosphorylation that lead to MCF7 cell apoptosis by inducing stress in the endoplasmic reticulum (ER). 24,25 However, it is not known whether CPT has any effects on estrogen-stimulated ER signaling and estrogen /ER mediated cancer cell growth.…”

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

“…CPT has been previously shown to inhibit growth and induce apoptosis in a number of human cancer cell lines [11]. In prostate cancer cells, CPT induced cell apoptosis by suppressing mammalian target of rapamycin (mTOR)-mediated cyclin D1 expression [12] and inhibiting Stat3 activity [13].…”

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

“…Most recently, data have shown that CPT is the most potent anticancer agent among the extracts of Danshen, by inhibiting proliferation of cancer cells or inducing cell apoptosis (Chen et al, 2010;Chen et al, 2012), but its function on MCF-7 cells still rarely reported. The (Nizamutdinova et al, 2008), therefore, it is important to identify new agents that is effective in breast cancers.…”

“…Considered that breast cancer is the most prevailing disease among all cancers (Soerjomataram et al, 2012), and previous reports have showed that CPT induces ROS release which activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death of human tumor cells (Rh30, DU145, and MCF-7) (Chen et al, 2012), we wondered is that possible CPT inhibits MCF7 cells grow in vivo? If so, how does it perform its antitumor function?…”