Cordyceps militarisExerts Antitumor Effect on Carboplatin-Resistant Ovarian Cancer via Activation of ATF3/TP53 Signaling In Vitro and In Vivo

Abstract

This study aimed to investigate the effect of Cordyceps militaris extract on the proliferation and apoptosis of carboplatin- resistant SKOV-3 and determine the underlying mechanisms for overcoming carboplatin resistance in human ovarian cancer. We cultured the carboplatin-resistant SKOV-3 cells in vitro until the exponential growth phase and then treated with different concentrations of C. militaris for 24, 48, and 72 hours. We performed cell proliferation assay, cell morphological change assessment using transmission electron microscopy, apoptosis assay, and immunoblotting to measure the protein expression of caspase-3 and -8, poly (ADP-ribose) polymerase (PARP)-1, B-cell lymphoma (Bcl)-2, and activating transcription factor 3 (ATF3)/TP53 signaling-related proteins. As a result, C. militaris reduced the viability of carboplatin-resistant SKOV-3 and induced morphological disruptions in a dose- and time-dependent manner. The gene expression profiles indicated a reprogramming pattern of the previously known and unknown genes and transcription factors associated with the action of TCTN3 on carboplatin-resistant SKOV-3 cells. We also confirmed the C. militaris-induced activation of the ATF3/TP53 pathway. Immunoblotting indicated that cotreatment of C. militaris and carboplatin-mediated ATF3/TP53 upregulation induced apoptosis in the carboplatin-resistant SKOV-3 cells, which are involved in the serial activation of pro-apoptotic proteins, including Bcl-2, Bax, caspases, and PARP-1. Further, when the ATF3 and TP53 expression increased, the CHOP and PUMA expressions were upregulated. Consequently, the upregulated CHOP/PUMA expression activated the positive regulation of the apoptotic signaling pathway. In addition, it decreased the Bcl-2 expression, leading to marked ovarian cancer cells sensitive to carboplatin by enhancing apoptosis. We then corroborated these results using in vivo experiments. Taken together, C. militaris inhibits carboplatin-resistant SKOV-3 cell proliferation and induces apoptosis possibly through ATF3/TP53 signaling upregulation and CHOP/PUMA activation. Therefore, our findings provide new insights into the treatment of carboplatin-resistant ovarian cancer using C. militaris.

A Network Pharmacology Study to Uncover the Mechanism of FDY003 for Ovarian Cancer Treatment

“…FDY003 and its active ingredients possess anti-OC properties. The growth-arrest and pro-apoptotic effects of Cm in OC cells are mediated by the pharmacological regulation of TNF-α, TNF receptor 1, NF-κB, activating transcription factor 3 (ATF3), caspase, poly ADP-ribose polymerase (PARP)-1, B-cell lymphoma (Bcl)-2, and Bcl-2-associated X protein (Bax) pathways 111,112 . Cordycepin targets Dickkopf-related protein 1 (Dkk1), autophagy-related protein 8 (ATG8), beclin, microtubule-associated protein 1A/1B-light chain 3 (LC3), β-catenin, matrix metalloproteinase (MMP), transforming growth factor (TGF)-β, vimentin, peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, E-cadherin, estrogen receptor (ER)-α, mitochondrial, CC chemokine ligand 5 (CCL5), Akt, NF-κB, the long form of cellular FLICE-inhibitory protein (c-FLIP L ), and caspase signaling of OC cells; these pharmacological effects inhibit the survival, self-renewal potential, viability, EMT, metastasis, therapeutic resistance, migration, and invasion of OC cells 113-116 .…”

Mychonastes sp. 247 Induces Apoptosis of A549 Human Lung Cancer Cells by Promoting STRA6-Mediated Reactive Oxygen Species Production

“…Quadrupole Time-of-Flight mass spectrometry was performed according to the procedures described in our previous study. 20 Briefly, liquid chromatography (LC) separation was performed with an Acquity I-Class UPLC (Waters Corp.) with an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 100 mm). A SYNAPT G2-Si system (Waters Corp.) with the MSe acquisition technique was used for MS detection.…”

Purification, characterization, antioxidant, and antitumor activity of polysaccharides isolated from silkworm cordyceps

“…Hence, for about two decades, many researchers have been focused on the medicinal properties of the metabolites of C. militaris (Matsuzawa, Furuya, & Hirotani, 1983; Mouri et al, 1991; Yuan, Zhang, Fan, & Yang, 2008; Zhang, Wen, Duan, Zhang, & Ma, 2019). Furthermore, many studies have confirmed that C. militaris has many striking bioactivities such as immunomodulatory (Liu et al., 2016), antitumor (Jo, Jang, Yang, Jang, & Park, 2020), anti‐aging(Ji, Jia, Li, Wang, & Cai, 2009), antioxidant (Chen, Wu, & Huang, 2013), anti‐inflammatory (Smiderle et al., 2014), anti‐influenza effects (Ohta et al, 2007), antifibrotic (Nan, Park, Yang, Song, Ko, & Sohn, 2001) and so on. However, the popularity and high demand for C. sinensis and C. militaris has led to the scarcity of them, leading to their classification as protected endangered species (Cunningham & Long, 2018).…”