Tanshinone IIA regulates colorectal cancer apoptosis via attenuation of Parkin‑mediated mitophagy by suppressing AMPK/Skp2 pathways

Abstract

Mitophagy is important for cancer development. Notably, the role of Parkin‑mediated mitophagy in colorectal cancer (CRC) mortality has not been fully determined. Therefore, the present study aimed to investigate the effect of Parkin‑mediated mitophagy on CRC apoptosis. In addition, the present study investigated the therapeutic effects of Tanshinone IIA (Tan IIA) on the regulation of CRC cell death via mitophagy. Cellular apoptosis was measured following Tan IIA treatment. In addition, mitophagy activity was evaluated by immunofluorescence and western blotting. The results of the present study revealed that Tan IIA may enhance CRC cell death. In addition, the results demonstrated that Tan IIA enhanced mitochondrial apoptosis, as demonstrated by reduced mitochondrial membrane potential, elevated mitochondrial permeability transition pore opening, and increased oxidative stress, mitochondrial energy disorder and proapoptotic factor expression. Furthermore, the results of the present study demonstrated that Tan IIA induced mitochondrial apoptosis via inhibition of mitophagy. In addition, it was revealed that mitophagy could suppress mitochondrial apoptosis. Functional assays revealed that Tan IIA suppressed the adenosine monophosphate‑activated protein kinase (AMPK) pathway, resulting in the inactivation of S‑phase kinase associated protein 2 (Skp2). Furthermore, reduced levels of Skp2 failed to activate Parkin, thus resulting in inhibition of mitophagy. Conversely, reactivation of AMPK and overexpression of Skp2 rescued mitophagy activity and thus attenuated the Tan IIA‑induced apoptosis of CRC cells. In conclusion, the results of the present study demonstrated the beneficial role of mitophagy in CRC cell survival and suggested that Tan IIA may be an effective therapeutic agent, which suppresses mitophagy activity and enhances CRC apoptosis.

Tanshinone IIA reduces SW837 colorectal cancer cell viability via the promotion of mitochondrial fission by activating JNK-Mff signaling pathways

“…no. 568–72-9) were incubated with cells for approximately 12 h. This concentration range was selected based on a previous study [ 36 ]. Meanwhile, the cells incubated with PBS were used as the control group.…”

The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients

“…In addition, Tan IIA might induce the autophagy in oral squamous cell carcinoma by both activating the Beclin-1/Atg7/Atg12-Atg5 pathway and inactivating the PI3K/Akt/mTOR pathway (Ye et al, 2018). Another recent study proved that Tan IIA suppressed colorectal cancer cell growth, decreased mitochondrial membrane potential, and inhibited mitophagy through inactivation of AMPK/Skp1/Parkin pathway (He and Gu, 2018).…”

“…In another research, Tan IIA increased p53, p21, and Bax; decreased B-cell lymphoma-2 (Bcl-2), cell division cycle gene 2 (cdc2), and cdc25 expression; and induced ER-related apoptosis in hepatocellular carcinoma 15 cells through the regulation of calreticulin, caspase-12, and GADD153 expression (Cheng and Su, 2010). Additionally, Tan IIA inhibited the protective mitophagy through the inhibition of the adenosine monophosphate-activated kinase (AMPK), S-phase kinase-associated protein 2 (Skp2), Parkin pathway, leading to the mitochondria-mediated apoptosis of cancer cells (He and Gu, 2018).…”

Tanshinone IIA combined with cisplatin synergistically inhibits non‐small‐cell lung cancer in vitro and in vivo via down‐regulating the phosphatidylinositol 3‐kinase/Akt signalling pathway

“…Many studies have demonstrated that Tan IIA results in an increased apoptosis rate in NSCLC (Chiu & Su, ), and colorectal carcinoma (He & Gu, ). Furthermore, Zhao found that Tan IIA could potentiate the apoptosis rate of DDP in pharyngeal squamous cell carcinoma (Zhao et al, ).…”

“…Tan IIA is prescribed for the treatment of cardiovascular disease in the pharmacopoeia of the People's Republic of China as the TCM “Danshen.” Tan IIA has been shown to exhibit antiangiogenic (Tsai, Yang, Wu, Pang, & Huang, ), antioxidant (Guo et al, ), anti‐inflammatory, immunomodulatory (Chen & Xu, ), and antitumor activities. A number of studies have shown that Tan IIA antagonizes the proliferation of multiple human cancer cell lines, such as human colorectal cancer (He & Gu, ; Sui et al, ), human gastric carcinoma (Su, ; Zhang et al, ), human pancreatic cancer (Chiu & Su, ), human breast cancer and (Li & Lai, ; Lv et al, ), and human osteosarcoma cells (Huang et al, ). However, the specific mechanisms of action underlying the anticancer effects of Tan IIA in NSCLC cells remain elusive.…”