Peroxidase from foxtail millet bran exerts anti-colorectal cancer activity via targeting cell-surface GRP78 to inactivate STAT3 pathway

Molecular targeted therapy has become an emerging promising strategy in cancer treatment, and screening the agents targeting at cancer cell specific targets is very desirable for cancer treatment. Our previous study firstly found that a secretory peroxidase of class III derived from foxtail millet bran (FMBP) exhibited excellent targeting anti-colorectal cancer (CRC) activity in vivo and in vitro, whereas its underlying target remains unclear. The highlight of present study focuses on the finding that cell surface glucose-regulated protein 78 (csGRP78) abnormally located on CRC is positively correlated with the anti-CRC effects of FMBP, indicating it serves as a potential target of FMBP against CRC. Further, we demonstrated that the combination of FMBP with the nucleotide binding domain (NBD) of csGRP78 interfered with the downstream activation of signal transducer and activator of transcription 3 (STAT3) in CRC cells, thus promoting the intracellular accumulation of reactive oxygen species (ROS) and cell grown inhibition. These phenomena were further confirmed in nude mice tumor model. Collectively, our study highlights csGRP78 acts as an underlying target of FMBP against CRC, uncovering the clinical potential of FMBP as a targeted agent for CRC in the future.

Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.

Regulation of Plasmodium falciparum cell cycle involving Cyclins and Cyclin Dependent Kinases

@#Protein kinases (PKs) are regulators of protein phosphorylation in many infectious diseases, including malaria. However, the cellular functions of majority of PKs in Plasmodium falciparum remain unknown. The mechanisms involved in P. falciparum cell cycle progress are not fully understood. The activation of cyclin-dependent kinases (CDKs), which constitute a PK family that includes crucial regulators of cell cycle progression in eukaryotes, is strictly being coordinated by the interaction with specific cyclins at well-defined points within the cell cycle. These cyclin/CDK complexes are very well characterised in humans, but little is known in P. falciparum. This review expand our understanding of the characteristic of CDKs and cyclins in P. falciparum, and paves the way for further investigations on the precise molecular role of these crucial regulatory proteins in mosquito and human. This represents a valuable step towards the elucidation of cell cycle control mechanisms in malaria parasites.

Role of RB in the cell cycle and its relation with colorectal cancer / 国际外科学杂志

Since its discovery, the retinoblastoma (RB) tumor-suppressor protein has become a focal point of caner and cell cycle research, and subsequently discovered members(pRB,p107,p103) of the RBfamily have been proved to play a important role in the cell cycle and the development of cancer. RB regulates the cell growth, development and differentiation via the interactions with E2f and some other cytokines,and its alternation even make the tumor formation. In comparison with some other tumors, colorectal cancer(CRC) has the different expression of RB.We may assume that the different causes of CRC and some unique functions of RB in CRC lead to the alternation.

8-Br-cAMP up-regulates antioncogene expression in human retinoblastoma HXO-Rb44 cells / 中华实验眼科杂志

It is kno wn that 8-Br-cAMP is one of selective bi nding site analogues for cAMP RIIα to af fect cell growth through regulation of g ene expression.The p16,p21wafl,p53 a nd Rb are antioncogenes which affect cel l growth through control of cell cycle.T he aim of this study is to investigate t he 8-Br-cAMP effect on the expression of antioncogenes in human HXO-Rb44 cells. Methods Cultured HXO-Rb44 cells in RPMI -1 640 medium were divided into two aliquot s.8-Br-cAMP (2×10-5mol/L) was added i nto one aliquot for 24h as the experime ntal group(EG),the another aliquot witho ut 8-Br-cAMP as the control group(CG).Af ter 24h,the cell suspension was dropped onto the nitrocellulose membrane.The mR NA of p16,p21wafl,wild type(w)p53,mut ant type(m) p53 and Rb were used respec tively with biotin-labeled cDNA probes b y intact cell RNA dot blot.The immunorea ctivity(IR) of P16,P21wafl,PRb,PCN A,cdk2 and cdk4 were detected respecti vely with specific monoclonal antibodies on dot blot.ResultsThe mRNA dot blot s ignals of mp53 and protein dot blot of cdk2-IR,cdk4-IR and PCNA-IR in EG were weaker than those in CG(P＜0.05～0.01). W hile,the mRNA signals of p16,p21wafl,wp53 and Rb in EG were stronger than tho se in CG(P＜0.05～0.01).The intensity of ea ch protein dot blot was consistent with that of their RNA dot blot (except for w P53-IR and mP53-IR not to be done).Conc lusions(1)8-Br-cAMP could up-regul ate expression of antioncogenes includin g p16,p21wafl,wp53,Rb,and protein exp ression of P16,P21wafl and PRb.(2) 8-Br-cAMP could down-regulate mp53 gene expression and protein expression of cd k2,cdk4 and PCNA.The results suggest t hat 8-Br-cAMP could inhibit human HXO-Rb 44 cell growth through interfering rela ted gene expression of cell cycle.

Cyclins/CDKs and antitumor activity of their inhibitors / 中国癌症杂志

Cyclins, CDKs and CKIs in cell cycle play important roles in maintaining cell cycle and regulation of the process cell cycle. Many endogenous and extraneous inhibitors have effects on cell cycle by modulating functions of cyclins, CDKs and CKIs. Several highlighted points in the researches of cell cycle and related proteins, inhibitors were reviewed, including the latest advances on their applications in cancer therapy.