Physapubescin B inhibits tumorgenesis and circumvents taxol resistance of ovarian cancer cells through STAT3 signaling

Abstract

Ovarian cancer is the most lethal gynaecological malignancy. Recurrence and subsequent resistance to chemotherapy have become major obstacles to treating these diseases. In the present study, we showed that a natural withanolide isolated from the plant Physalis pubescens L. (Solanaceae), Physapubescin B, exhibited potent anti-tumor activity against ovarian cancer cells. Physapubescin B promoted apoptosis, induced cell-cycle arrest and inhibited invasion of ES-2 and A2780 cells. Physapubescin B treatment also resulted in suppression of the transcriptional activity of STAT3, an oncogenic transcription factor activated in many human malignancies including ovarian cancer, through disturbing the dimerization of STAT3, and thereby inhibited the nuclear translocation of Tyr705/Ser727-phosphorylated STAT3. The IL-6-stimulated activation of STAT3 and its downstream genes Cyclin D1, survivin, and Bcl-xL was also repressed by Physapubescin B. Furthermore, Physapubescin B sensitizes A2780 cells to taxol-induced cell growth inhibition in vitro. These findings strongly suggest that Physapubescin B has potential antitumor activity and may circumvent taxol resistance in human ovarian cancer cells through inhibition of aberrant activation of STAT3.

Withanolides: Promising candidates for cancer therapy

“…Both the in vitro and in vivo investigations illustrated that withano- Hsu et al, 2012;Lee et al, 2017;Lee et al, 2022;Ma et al, 2016;Mondal et al, 2010;Rao et al, 2016;Stan et al, 2008;Wu et al, 2012;Yu et al, 2017;Zhao et al, 2017) cytostatic autophagy (Ma et al, 2017;Rah et al, 2015;Xu et al, 2017;Yu et al, 2017), whereas our group previously found that the cytoprotective autophagy was initiated by physalin A (He, Zang, Feng, Wang, et al, 2013). Intriguingly, withaferin A is quite distinctive since the autophagy induced by withaferin A was cytoprotective in prostate cancer cells , and in breast cancer cells (Muniraj et al, 2019).…”

“…Cell division is strictly controlled by a series of highly evolutionarily conserved cell cycle machinery, and cancer is increasingly being regarded as a cell-cycle disease, in which the operation of the accurate machinery is disrupted or breached, occasioning aberrant cell divisions (Matthews et al, 2022). There is mounting evidence indicating frequent overexpression of cyclin D/E, PLK1 (polo-like kinase 1), Aurora A/B, Skp2, and Cdc20 in various human cancer cell types (Liu et al, 2022) (Chang et al, 2007;Park et al, 2016;Perestelo et al, 2019;Zhao et al, 2017).…”

“…JAKs phosphorylate themselves and the intracellular portion of receptors, which recruit STATs to be phosphorylated (Schwartz et al, 2016). As a transcriptional factor to execute the corresponding functions, STATs could be inhibited by withaferin A (Choi & Kim, 2015), physalin A (Zhu et al, 2016), tubocapsenolide A (Zhu et al, 2021), withanolide D (Mu et al, 2018), and physapubescin B (Zhao et al, 2017) through regulation of phosphorylation, inhibition of nuclear translocation and transcription.…”

“…Activation of BAX and BAK can lead to the formation of pores in the outer membrane of mitochondria, which can touch off the cytochrome c release. Withaferin A, physagulide P, withametelin, withanolide D, 4β‐hydroxywithanolide E, physapubescin, physapubescin B, physapubenolide, physalin A, physalin B, physalin F, and withagenin A diglucoside can initiate intrinsic mitochondrial apoptosis by up‐regulating BAX (Chen, Xia, Qiu, et al, 2016; He, Zang, Feng, Chen, et al, 2013; Hsu et al, 2012; Lee et al, 2017; Lee et al, 2022; Ma et al, 2016; Mondal et al, 2010; Rao et al, 2016; Stan et al, 2008; Wu et al, 2012; Yu et al, 2017; Zhao et al, 2017) to trigger apoptosis. Recently, using small RNA next‐generation sequencing (NGS) and qRT‐PCR technology, Shuaib et al found that the co‐treatment strategy of withaferin A and miR‐181c‐5p mimic showed a pronounced anticancer effect by inducing the intrinsic apoptosis pathway in TNBC cells by upregulating the caspase‐8 and its downstream targets (Shuaib et al, 2022).…”

“…Among them, withaferin A plays an extensive interruptive role in cell cycle arrest, which could also result in an arrest in the G1 phase. Besides, tubocapsanolide A, withaferin A‐Sily, physapubescin B, and 4β‐hydroxywithanolide E exhibit a growth inhibitory effect on cancer cells by inducing G0/G1 cell cycle arrest (Chang et al, 2007; Park et al, 2016; Perestelo et al, 2019; Zhao et al, 2017).…”