Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

https://www.mdpi.com/1422-0067/22/12/6434/pdf

Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in the cure of colon cancer. Therefore, there is an urgent need to explore a safe and effective multidrug resistance reversal agent for colorectal cancer, which would be of great significance for improving clinical efficacy. The dietary flavonoid kaempferol plays a key role in the progression of colorectal cancer and 5-Fu resistance. However, the molecular mechanism of kaempferol in reversing 5-Fu resistance in human colorectal cancer cells is still unclear. We found that kaempferol could reverse the drug resistance of HCT8-R cells to 5-Fu, suggesting that kaempferol alone or in combination with 5-Fu has the potential to treat colorectal cancer. It is well known that aerobic glycolysis is related to tumor growth and chemotherapy resistance. Indeed, kaempferol treatment significantly reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells. In terms of mechanism, kaempferol promotes the expression of microRNA-326 (miR-326) in colon cancer cells, and miR-326 could inhibit the process of glycolysis by directly targeting pyruvate kinase M2 isoform (PKM2) 3′-UTR (untranslated region) to inhibit the expression of PKM2 or indirectly block the alternative splicing factors of PKM mRNA, and then reverse the resistance of colorectal cancer cells to 5-Fu. Taken together, our data suggest that kaempferol may play an important role in overcoming resistance to 5-Fu therapy by regulating the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.

/pdf/kaempferol-can-reverse-the-5-fu-resistance-of-colorectal-2lvhgsob.pdf

Kaempferol Can Reverse the 5-Fu Resistance of Colorectal Cancer Cells by Inhibiting PKM2-Mediated Glycolysis

Kaempferol and its derivatives are naturally occurring phytochemicals with promising bioactivities. This flavonol can reduce the lipid oxidation in the human body, prevent the organs and cell structure from deterioration and protect their functional integrity. This review has extensively highlighted the antioxidant, antimicrobial, anticancer, neuroprotective, and hepatoprotective activity of kaempferol. However, poor water solubility and low bioavailability of kaempferol greatly limit its applications. The utilization of advanced delivery systems can improve its stability, efficacy, and bioavailability. This is the first review that aimed to comprehensively collate some of the vital information published on biosynthesis, mechanism of action, bioactivities, bioavailability, and toxicological potential of kaempferol. Besides, it provides insights into the future direction on the improvement of bioavailability of kaempferol for wide applications.

Kaempferol: A flavonoid with wider biological activities and its applications.

Background Small nucleolar RNA host gene (SNHG) long noncoding RNAs (lncRNAs) are frequently dysregulated in human cancers and involved in tumorigenesis and progression. SNHG17 has been reported as a candidate oncogene in several cancer types, however, its regulatory role in colorectal cancer (CRC) is unclear. Methods SNHG17 expression in multiple CRC cohorts was assessed by RT-qPCR or bioinformatic analyses. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8) and colony formation assays. Cell mobility and invasiveness were assessed by Transwell assays. Tumor xenograft and metastasis models were applied to confirm the effects of SNHG17 on CRC tumorigenesis and metastasis in vivo. Immunohistochemistry staining was used to measure protein expression in cancer tissues. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of SNHG17 in CRC. Results Using multiple cohorts, we confirmed that SNHG17 is aberrantly upregulated in CRC and correlated with poor survival. In vitro and in vivo functional assays indicated that SNHG17 facilitates CRC proliferation and metastasis. SNHG17 impedes PES1 degradation by inhibiting Trim23-mediated ubiquitination of PES1. SNHG17 upregulates FOSL2 by sponging miR-339-5p, and FOSL2 transcription activates SNHG17 expression, uncovering a SNHG17-miR-339-5p-FOSL2-SNHG17 positive feedback loop. Conclusions We identified SNHG17 as an oncogenic lncRNA in CRC and identified abnormal upregulation of SNHG17 as a prognostic risk factor for CRC. Our mechanistic investigations demonstrated, for the first time, that SNHG17 promotes tumor growth and metastasis through two different regulatory mechanisms, SNHG17-Trim23-PES1 axis and SNHG17-miR-339-5p-FOSL2-SNHG17 positive feedback loop, which may be exploited for CRC therapy.

SNHG17 promotes colorectal tumorigenesis and metastasis via regulating Trim23-PES1 axis and miR-339-5p-FOSL2-SNHG17 positive feedback loop.

Natural compounds have always represented valuable allies in the battle against several illnesses, particularly cancer. In this field, flavonoids are known to modulate a wide panel of mechanisms involved in tumorigenesis, thus rendering them worthy candidates for both cancer prevention and treatment. In particular, it was reported that flavonoids regulate apoptosis, as well as hamper migration and proliferation, crucial events for the progression of cancer. In this review, we collect recent evidence concerning the anti-cancer properties of the flavonols myricetin and kaempferol, discussing their mechanisms of action to give a thorough overview of their noteworthy capabilities, which are comparable to those of their most famous analogue, namely quercetin. On the whole, these flavonols possess great potential, and hence further study is highly advised to allow a proper definition of their pharmaco-toxicological profile and assess their potential use in protocols of chemoprevention and adjuvant therapies.

/pdf/molecular-pathways-involved-in-the-anti-cancer-activity-of-3vl66x5c.pdf

Molecular Pathways Involved in the Anti-Cancer Activity of Flavonols: A Focus on Myricetin and Kaempferol

Colon cancer is an aggressive malignancy with very limited therapeutic approaches. The available therapeutic agents for colon cancer show strong adverse effects and poor effectiveness, indicating the urgent need to identify new therapeutic drugs for this malignancy. Kaempferol, a flavonoid found in a variety of natural foods, exhibits significant inhibitory effects on colon cancer. Here, it was found that kaempferol inhibited the proliferation of human colon cancer cells HCT116 and DLD1 in a dose-dependent manner, and the IC50 values were 63.0 ± 12.9 and 98.3 ± 15.9 μM, respectively. Also, kaempferol treatment delayed G1 phase progression of cell cycle and induced apoptosis. Aerobic glycolysis is the major energy source for various tumor growths, including colon cancer. Indeed, kaempferol treatment impaired glucose consumption, which subsequently led to reduced lactic acid accumulation and ATP production. Mechanistically, kaempferol promoted the expression of miR-339-5p. Further studies identified hnRNPA1 and PTBP1 as two direct targets of miR-339-5p. By directly targeting hnRNPA1 and PTBP1, miR-339-5p reduced the expression of M2-type pyruvate kinase (PKM2) but induced that of PKM1. In conclusion, these data demonstrate that by modulating miR-339-5p-hnRNPA1/PTBP1-PKM2 axis, kaempferol inhibits glycolysis and colon cancer growth, which reveals a new explanation for the molecular mechanism underlying kaempferol anti-tumor.

Chenglu Li

Papers

Kaempferol Reverses Aerobic Glycolysis via miR-339-5p-Mediated PKM Alternative Splicing in Colon Cancer Cells

Polyphenols from Hippophae rhamnoides suppressed colon cancer growth by regulating miRNA-mediated cell cycle arrest and apoptosis in vitro and in vivo