Insulin enhancement of the antitumor activity of chemotherapeutic agents in colorectal cancer is linked with downregulating PIK3CA and GRB2

Abstract

The present state of cancer chemotherapy is unsatisfactory. New anticancer drugs that marginally improve the survival of patients continue to be developed at an unsustainably high cost. The study aimed to elucidate the effects of insulin (INS), an inexpensive drug with a convincing safety profile, on the susceptibility of colon cancer to chemotherapeutic agents: 5-fluorouracil (FU), oxaliplatin (OXA), irinotecan (IRI), cyclophosphamide (CPA) and docetaxel (DOC). To examine the effects of insulin on cell viability and apoptosis, we performed an in vitro analysis on colon cancer cell lines Caco-2 and SW480. To verify the results, we performed in vivo analysis on mice bearing MC38 colon tumors. To assess the underlying mechanism of the therapy, we examined the mRNA expression of pathways related to the signaling downstream of insulin receptors (INSR). Moreover, we performed Western blotting to confirm expression patterns derived from the genetic analysis. For the quantification of circulating tumor cells in the peripheral blood, we used the maintrac method. The results of our study show that insulin-pretreated colon cancer cells are significantly more susceptible to commonly used chemotherapeutics. The apoptosis ratio was also enhanced when INS was administered complementary to the examined drugs. The in vivo study showed that the combination of INS and FU resulted in significant inhibition of tumor growth and reduction of the number of circulating tumor cells. This combination caused a significant downregulation of the key signaling substrates downstream of INSR. The results indicate that the downregulation of PIK3CA (phosphatidylinositol 3-kinase catalytic subunit alpha), which plays a critical role in cell signaling and GRB2 (growth factor receptor-bound protein 2), a regulator of cell proliferation and differentiation may be responsible for the sensitizing effect of INS. These findings were confirmed at protein levels by Western blotting. In conclusion, these results suggest that INS might be potentially applied to clinical use to enhance the therapeutic effectiveness of chemotherapeutic drugs. The findings may become a platform for the future development of new and inexpensive strategies for the clinical chemotherapy of tumors.

Randomised controlled trial of intermittent vs continuous energy restriction during chemotherapy for early breast cancer

“…Our timing of energy restriction prior to, but not after, chemotherapy administration avoids any theoretical reductions in cytotoxic effects on cancer cells alongside reductions in mitogens like insulin and IGF-1 and the available pool of proliferating cells as reported in preclinical studies with doxorubicin, fluorouracil, cyclophosphamide and docetaxel [ 51 , 52 ]. However, our timing could miss any potential synergistic effects between energy restriction and chemotherapy.…”

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

“…Recently, its tumor-promoting effects were shown in many malignancies including lung cancer (Yang et al, 2017a;Jiang et al, 2018;Mitra et al, 2018;Wang and Wang, 2020), gastric cancer (Ye et al, 2018), colorectal cancer (Ding et al, 2019), ovarian carcinoma (Huang et al, 2018), renal cell carcinoma (Gu et al, 2017), breast cancer (Lim et al, 2000;Haines et al, 2014;López-Cortés et al, 2020), and esophageal squamous cell carcinoma (Shi et al, 2018). In addition, in lung cancer (Chen et al, 2020), ovarian cancer (Xu et al, 2018), colorectal cancer (Agrawal et al, 2019), and breast cancer (Chen et al, 2018), its associations with the resistance of the tumors to chemotherapeutic drugs were presented, and its downregulation could reverse the resistant status or enhance the sensitivity to the drugs, indicating its potential as a chemotherapeutic target in the malignancies. Here, we presented the overexpression of GRB2, its positive correlation with cell proliferation marker MKI67, and its unfavorable prognostic roles in HCC, indicating its associations with HCC development and progression, consistent with the tumor-promoting activity of GRB2 in HCC reported in recent studies (Yang et al, 2018;Lv et al, 2020;Sun et al, 2020).…”

A Deep Learning Framework for Prediction of Clinical Drug Response of Cancer Patients and Identification of Drug Sensitivity Biomarkers using Preclinical Samples

“…Indeed, several studies have suggested a correlation between expression of ARF6 and invasion and metastasis of multiple cancers [50–52], suggesting that antagonistic ARF6 signaling can dictate TMV shedding and the overall mode of invasion. Insulin, a signaling molecule that controls systemic metabolic homeostasis, can be seen as enabling tumour development by providing a mechanism for PI3K activation and enhanced glucose uptake [53–58] and plays a role in cytotoxic therapy response [59]. RalA (RAS Like Proto-Oncogene A) is a member of the Ral family, and the RalA pathway contributes to anchorage independent growth, tumorigenicity, migration and metastasis [60–64].…”