Surfactin induces ER stress‐mediated apoptosis via IRE1‐ASK1‐JNK signaling in human osteosarcoma

Abstract

Osteosarcoma, one of primary bone tumor in children and young adults, has poor prognosis and drug resistances to chemotherapy. In order to reinforce the conventional therapies and antagonize the osteosarcoma in patients, a novel strategy is required for developing a new treatment. In this study, surfactin, a natural product from Bacillus subtilis, showed the efficiency of cell death in osteosarcoma, but not in normal cells. Surfactin triggers ER stress mechanism by promoting the aberrant Ca2+ release from ER lumen and ER‐signaling to mitochondrial dysfunction following caspases activation mediating cell apoptosis. Surfactin‐induced ER stress not only upregulated of glucose‐regulated protein 78/94 and IRE1‐ASK1‐JNK pathway but also leading to calpains and Bcl‐2 proteins family involving the release of cytochrome c. The releases into cytosol trigger the cleavage of caspase‐9 and caspase‐3 to induce cell apoptosis. In this study, surfactin demonstrated the potential functions to trigger the ER stress, ER stress‐associated IRE1‐ASK1‐JNK signaling pathway, mitochondrial dysfunction, and caspase activations leading to programmed cell apoptosis. Importantly, implicating the signaling pathway that regulates the connection between ER stress and mitochondrial dysfunction causing apoptosis associated with surfactin. These results indicated a potential application of surfactin strengthen current conventional therapies.

Molecularly Engineered Surfactin Analogues Induce Nonapoptotic-Like Cell Death and Increased Selectivity in Multiple Breast Cancer Cell Types

“…After evaluating IC 50 values against the four tumorigenic cell lines and two nontumorigenic lines, the most promising cationic, amplified anionic, and neutral synthetic surfactin drug candidates (see above), based on the overall activity and SI values (see above) as well as 1 , were investigated to elucidate mechanism(s) by which they inhibit breast cancer cell growth. For 1 , previous reports on the operative mechanisms for cell killing include allergic reactions through ROS-regulated apoptosis, , disruptions to plasma membrane composition, and ER-stress-mediated apoptosis …”

“…For 1, previous reports on the operative mechanisms for cell killing include allergic reactions through ROS-regulated apoptosis, 43,44 disruptions to plasma membrane composition, 18 and ER-stress-mediated apoptosis. 19 We investigated whether elevated levels of caspase-3 and caspase-7 are found in cell media post 24 h of drug exposure for BT-474 and MDA-MB-231 cell lines to determine if apoptosis was a major cause of cell death, as previously claimed by others. 45,46 Caspase-3 controls morphological changes in apoptosis and DNA fragmentation, while caspase-7 is believed to have greater importance in the loss of cellular viability.…”

“…Not only are current treatment options expensive but they typically rely on nontargeted chemotherapeutics such as doxorubicin or paclitaxel . Surfactin has been reported to cause cell cycle arrest, antiproliferation, and apoptosis in human colon carcinoma, human breast cancer, , ovarian cancer, and osteosarcoma . Surfactin is selective for tumorigenic over nontumorigenic cell lines when treated at an established therapeutic IC 50 , including 100% cell viability for nontumorigenic keratinocytes (30 μM) compared against oral squamous cells and osteoblasts (5 μM) compared against osteosarcoma .…”

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma

“…In addition, the IRE1-ASK1-JNK pathway is typically involved in cell death via ERS; in this pathway, IRE1α activates ASK1 and thus JNK, and JNK phosphorylation inhibits and activates Bcl-2 and Bim, respectively, which eventually leads to cell death. The therapeutic effect of this treatment on osteosarcoma can be investigated, and relevant targeted drug studies have been conducted on this [ 130 , 156 , 157 ].…”

Propofol Regulates ER Stress to Inhibit Tumour Growth and Sensitize Osteosarcoma to Doxorubicin

“…Endoplasmic reticulum (ER) is involved in the biosynthesis of lipids and proteins, and many factors or drugs could lead to "ER stress," a state induced by the accumulation of misfolded and/or unfolded proteins [20]. ER stressinduced osteosarcoma cell death was extensively reported [21][22][23][24][25][26].…”