Kaempferia parviflora Extract Inhibits STAT3 Activation and Interleukin-6 Production in HeLa Cervical Cancer Cells.

Kaempferia parviflora (KP) has been reported to have anti-cancer activities. We previously reported its effects against cervical cancer cells and continued to elucidate the effects of KP on inhibiting the production and secretion of interleukin (IL)-6, as well as its relevant signaling pathways involved in cervical tumorigenesis. We discovered that KP suppressed epidermal growth factor (EGF)-induced IL-6 secretion in HeLa cells, and it was associated with a reduced level of Glycoprotein 130 (GP130), phosphorylated signal transducers and activators of transcription 3 (STAT3), and Mcl-1. Our data clearly showed that KP has no effect on nuclear factor kappa B (NF-κB) localization status. However, we found that KP inhibited EGF-stimulated phosphorylation of tyrosine 1045 and tyrosine 1068 of EGF receptor (EGFR) without affecting its expression level. The inhibition of EGFR activation was verified by the observation that KP significantly suppressed a major downstream MAP kinase, ERK1/2. Consistently, KP reduced the expression of Ki-67 protein, which is a cellular marker for proliferation. Moreover, KP potently inhibited phosphorylation of STAT3, Akt, and the expression of Mcl-1 in response to exogenous IL-6 stimulation. These data suggest that KP suppresses EGF-induced production of IL-6 and inhibits its autocrine IL-6/STAT3 signaling critical for maintaining cancer cell progression. We believe that KP may be a potential alternative anti-cancer agent for suppressing cervical tumorigenesis.

Asiatic Acid, Corosolic Acid, and Maslinic Acid Interfere with Intracellular Trafficking and N-Linked Glycosylation of Intercellular Adhesion Molecule-1.

The pentacyclic triterpenoid ursolic acid was previously shown to inhibit the intracellular trafficking of intercellular adhesion molecule-1 (ICAM-1) from the endoplasmic reticulum (ER) to the Golgi apparatus. In the present study, we further investigated the biological activities of three pentacyclic triterpenoids closely related to ursolic acid on the interleukin 1α-induced expression and intracellular trafficking of ICAM-1. In human lung adenocarcinoma A549 cells, asiatic acid, corosolic acid, and maslinic acid interfered with the intracellular transport of ICAM-1 to the cell surface. Endoglycosidase H-sensitive glycans were linked to ICAM-1 in asiatic acid-, corosolic acid-, and maslinic acid-treated cells. Unlike corosolic acid, asiatic acid and maslinic acid increased the amount of the ICAM-1 protein. Moreover, asiatic acid increased the co-localization of ICAM-1 with calnexin (an ER marker), but not GM130 (a cis-Golgi marker). Asiatic acid, corosolic acid, and maslinic acid inhibited yeast α-glucosidase activity, but not Jack bean α-mannosidase activity. These results indicate that asiatic acid, corosolic acid, and maslinic acid interfere with the intracellular transport of ICAM-1 to the cell surface and cause the accumulation of ICAM-1 linked to endoglycosidase H-sensitive glycans.

Glucosidase II exhibits similarity to the p53 tumor suppressor in regards to structure and behavior in response to stress signals: a potential novel cancer biomarker.

Early diagnosis of cancer is a key factor for the success of treatment. For this reason, identification of highly sensitive and specific novel tumor markers is urgently needed. In the present study, the CM5 polyclonal antibody (CM5 pAb) raised against p53 of mouse origin was used to identify p53 structurally related protein(s) that may also play an important role in promoting or preventing lung cancer. Western blot analysis was performed on tumor tissues and corresponding normal tissues obtained from lung cancer patients. CM5 pAb reacted with a human protein with an apparent molecular weight of 90 kDa in the lung tumor tissue. The levels of this protein were greatly increased in 35 of the 37 (94.6%) lung tumor samples assessed, with only minimal expression in the normal adjacent tissues. The 90-kDa protein was immunoprecipitated by CM5 pAb and was subsequently identified by LC-MS/MS to be glucosidase II, a key protein involved in the quality control mechanism of glycoprotein folding. An investigation of the response to genotoxic stress and endoplasmic reticulum (ER) stress using A549 human lung adenocarcinoma cells demonstrated that glucosidase II exhibited a similar pattern of response as the p53 tumor suppressor. Protein levels of both p53 and glucosidase II were increased in response to UV irradiation but decreased in response to tunicamycin-induced ER stress. In conclusion, we demonstrated that a polyclonal antibody raised against mouse p53 could cross-react with human glucosidase II, which was found to be frequently overexpressed in human lung tumor tissues and exhibited a stress response similar to p53. The high frequency of glucosidase II overexpression, which to the best of our knowledge has not been previously described, indicates its crucial roles in lung tumorigenesis and is thus a valuable biomarker for facilitating the screening and/or diagnosis of lung cancer. However, further investigations concerning its relationship to p53 and its roles in ER and genotoxic stress are warranted.