This article **"The Monastery of Life Sciences**
Globally, cancer is the leading cause of death and one of the biggest barriers to increasing life expectancy for decades. In 2020 alone, a staggering 19.3 million new cancer cases were reported, resulting in nearly 10 million deaths. Throughout history, natural products have become a valuable resource for drug development for a variety of human diseases, with a particular focus on anti-cancer chemotherapy drugs. Their contribution is enormous and continues to hold great promise in the fight against cancer. Microcolloids and Majusculamide D are a series of compounds with similar structures isolated from the marine cyanobacteria moorea producens (formerly Lyngbya majuscula). Since 1988, Microcolin A-D and Majusculamide D have been isolated, and subsequent biological studies have shown that these compounds exhibit broad antitumor activity against different types of human cancer cells in vitro. In 2019, a total of 9 strains of the novel Microcolin E-M were isolated and showed significant cytotoxic activity against lung cancer cells, therefore, previous studies have suggested the potential of Microcolins in exploring anti-cancer strategies.
AutophagyIt is a fundamental physiological process that plays a vital role in maintaining cellular homeostasis. It involves the degradation and recycling of cellular components, such as proteins and damaged organelles, through a process of self-digestion. This process is conserved in all eukaryotic cells and serves as an important mechanism for new cell generation. Autophagy is involved in the regulation of cellular metabolism and energy control through the removal of protein aggregates, defective organelles and intracellular pathogens through intracellular components and metabolites, and is closely related to cell protection and cell death. Multiple stress states upregulate autophagic flux, such as nutrient deprivation, metabolism, oxidation, pathogens, DNA damage, and proteotoxic cues. Autophagy plays a vital role in the occurrence and development of a variety of metabolic diseases. This highly dynamic process is intrinsically linked to the regulation of immunity, neurodegenerative diseases, heart disease, and especially cancer. In tumors, many studies have shown that autophagy has a dual function at different stages of tumorigenesis: activation of autophagy promotes tumor cell survival during tumor progression (protective autophagy) or tumor cell death during the initial stages of tumorigenesis (cytotoxic nonprotective autophagy). There is no doubt that cytotoxic autophagy has great potential in the field of anti-cancer research. A large body of evidence supports that enhanced autophagy can be used as a measure to prevent cancer development, especially in precancerous lesions. Several approved drugs, experimental drugs, and natural compounds (such as metformin, curcumin, quercetin, and gemcitabine) can induce autophagy in different types of cancer. Other autophagy inducers (e.g., obatoclax, vitamin D analogues, and rapamycin) increase cancer cell death when combined with radiation and chemotherapy. Therefore, activation of autophagy may be an effective strategy, and there is an urgent need to develop new and more potent inducers of autophagy for tumors**.
Phosphatidylinositol transfer protein (PITIP).It is a soluble protein that is widely found in eukaryotes. Mammalian PIPs and binds and transfers phosphatidylinositol (PI) and phosphatidylcholine (PC) from the endoplasmic reticulum (ER) to various cell membranes. There is growing evidence that PITAPS is a potential target for a variety of diseases, such as cancer, neurodegenerative diseases, Duchenne muscular dystrophy, inflammation, and cardiovascular disease.
In order to deeply explore its anti-tumor activity and mechanism, the total synthesis of Microcolin H molecule was first realized with a single yield of more than 200 mg, which effectively solved the problem of substances of this kind of natural products. Secondly, at the cellular level, microcolin H has been found to have nanomolar inhibitory activity against various tumor cells such as gastric cancer, lung cancer, pancreatic cancer, and liver cancer. Furthermore, the direct target of microcolin H was found to be phosphatidylinositol transporter (PITIP) by applying chemical proteomics techniques. Protein thermostability experiments, molecular dynamics simulations, and knockout of PitP in gastric cancer cells led to loss of Microcolin H response were used to confirm that PITpp is a direct target of Microcolin H to exert antitumor activity.
Autophagy is a metabolic process of cellular self-degradation, by inducing autophagy, abnormal proteins and organelles in tumor cells can be removed, blocking the survival and spread of tumors, and providing new strategies and pathways for tumors. This study found that Microcolin H could significantly induce the conversion of LC3 to LC3 in tumor cells, and increase the formation and accumulation of autophagosomes in GFP-RFP-HeLa cells. Knockdown of Pitp Pitp leads to the emergence of an autophagic phenotype and loss of response to Microcolin H treatment, making it clear that Microcolin H induces autophagy and death of tumor cells. Finally, microcolin H also showed good antitumor activity in animal models, with a tumor suppression rate of 74 in the 10 mg kg** groupAt the same time, the autophagy inhibitor HCQ significantly weakened the anti-tumor effect of Microcolin H in vivo, further proving that Microcolin H exerts anti-tumor activity by inducing autophagy.
Figure 1The peptide microcolin H acts on PIPP-induced autophagy to exert antitumor activity.
This illustration was created by the Gethor Biographics team
This work was supported by the Peptide Innovation Unit of the Chinese Academy of Medical Sciences (IRT 15R27), the Medical and Health Science and Technology Innovation Project of the Chinese Academy of Medical Sciences (2019-I2M-5-074, 2021-I2M-1-026, 2021-I2M-3-001, 2022-I2M-2-002) and the ** Fundamental Research Funds for Universities (LZUJBKY-2023-11, LZUJBKY-2023-CT02, lzujbky-2023-IT19), the National Natural Science of China (21807053). Ph.D. student, School of Basic Medical Sciences, Lanzhou UniversityYang HangeZhang XiaoweiWang CongandZhang HailongThe associate professor is the co-first author. Associate Professor Yi Juan from the School of Basic Medical Sciences of Lanzhou University, Associate Professor Jin Xiaojie from Gansu University of Traditional Chinese Medicine, Researcher Hu Kuan from the Institute of Materia Medica, Chinese Academy of Medical Sciences and Wang Kun, a doctoral student, have made important contributions to this program. In addition, I would like to thank Professor Wang Chu of Peking University for his support in mass spectrometry.
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