Senescence Inducer Shikonin ROS-Dependently Suppressed Lung Cancer Progression

Abstract

Lung adenocarcinoma (LAC), predominant subclassfication of lung cancer, leads high incidence and mortality annually worldwide. During the premalignant transition from lung adenomas to LAC, cellular senescence is regard as a critical physiological barrier against tumor progression. Nevertheless, the role of senescence in tumorigenesis is controversial and few senescence inducers are extensively determined. In this study, we used two classical cell lines A549 and H1299 and two NSCLC xenograft models on Balb/c-nude mice to reveal the pro-senescence effects of shikonin and the corresponding underlying mechanism in LAC. Shikonin, a pure compound isolated from the herbal medicine Lithospermum erythrorhizon, remarkably stimulated cellular senescence including increased SAHF formation, enlarged cellular morphology, and induced SA-β-Gal positive staining. Further mechanism study revealed that the pro-senescence effect of shikonin was dependent on the increased intercellular ROS generation, which subsequently triggered DNA damage-p53/p21waf axis without activating oncogenes such as Ras and MEK-1. Meanwhile, Kdm2b, an H3K36me2-specific demethylase effectively suppressed ROS generation, was also notably suppressed by shikonin treatment. Moreover, shikonin at 10 mg/kg significantly inhibited tumor weights by 55.84% and 50.98% in A549 and H1299 xenograft model, respectively (P < 0.05) through activating cellular senescence. Our study suggested that shikonin, a ROS-dependent senescence inducer, could serve as a promising agent for further lung cancer treatment.

Antitumor Effect of Shikonin, a PKM2 Inhibitor, in Cholangiocarcinoma Cell Lines

“…Inhibition of CCA cell proliferation and migration by shikonin were rescued by NAC treatment. These results are consistent with previous reports showing that shikonin inhibited cell growth and induced apoptosis of CCA cells via increased ROS(37,38). ROS plays an important role in various diseases, including cancer mediated by different mechanisms and signaling pathways involved in cell proliferation, migration, apoptosis, and senescence.…”

“…ROS plays an important role in various diseases, including cancer mediated by different mechanisms and signaling pathways involved in cell proliferation, migration, apoptosis, and senescence. In cancer suppression, shikonin induced ROS to cytotoxic levels, resulting in inhibition of cell proliferation, migration, invasion and chemoresistance, whereas it induced cell senescence and apoptosis in several cancer types(37)(38)(39).…”

Intimate Relations—Mitochondria and Ageing

“…Senescent cells are themselves a source of ROS as a result of their dysfunctional mitochondria [ 325 ] and ROS-dependent feedback loops can positively reinforce the senescence pathway [ 325 , 326 ]. One trigger of the DNA damage response and induction of senescence is the telomere shortening mentioned above.…”

The Histone Code of Senescence

“…In addition, mitochondrial dysfunctions in IMR90 human fibroblasts lead to the ROS-JNK retrograde signaling pathways, which promote SASP and drive cytoplasmic chromatin fragments (CCFs) [133]. Importantly, the epigenetic homeostasis perturbation, achieved through HMTs or HDACs inhibition [129], is reported to expose cells to endogenous ROS production [134] or to trigger and sustain the senescence induced by the treatment with oxidative compounds [135]. In particular, some ROS generators inhibit PRC2 methyltransferases to allow the focused demethylation and transcriptional activation of CDKi [132].…”