Matrine suppresses KRAS‐driven pancreatic cancer growth by inhibiting autophagy‐mediated energy metabolism

Abstract

Matrine is a natural compound extracted from the herb Sophora flavescens Ait which is widely used in traditional Chinese medicine for treating various diseases. Recently, matrine was reported to have antitumor effects against a variety of cancers without any obvious side effects; however, the molecular mechanisms of its antiproliferative effects on cancer are unclear. Here, we report that matrine inhibits autophagy‐mediated energy metabolism, which is necessary for pancreatic cancer growth. We found that matrine significantly reduces pancreatic cancer growth in vitro and in vivo by insufficiently maintaining mitochondrial metabolic function and energy level. We also found that either pyruvate or α‐ketoglutarate supplementation markedly rescues pancreatic cancer cell growth following matrine treatment. Inhibition of mitochondrial energy production results from matrine‐mediated autophagy inhibition by impairing the function of lysosomal protease. Matrine‐mediated autophagy inhibition requires stat3 downregulation. Furthermore, we found that the antitumor effect of matrine on pancreatic cancer growth depends on the mutation of the KRAS oncogene. Together, our data suggest that matrine can suppress the growth of KRAS‐mutant pancreatic cancer by inhibiting autophagy‐mediated energy metabolism.

<p>Matrine Restrains Cell Growth and Metastasis by Up-Regulating LINC00472 in Bladder Carcinoma</p>

“…As a type of extract of Chinese traditional medicine radix sophorae flavescentis, researches had pointed out that MAT could induce cell apoptosis 26 and played a protective role in carcinoma. For instance, a research pointed out that MAT restrained cell proliferation in pancreatic carcinoma 27 while the other research pointed out that MAT restrained cell migration in lung carcinoma. 28 More interesting, in an animal model of bladder tumor, Gao et al pointed out that MAT could suppress bladder tumor invasion via regulation of the cyclooxygenase-2 (COX-2), and cytosolic recombinant phospholipase A2 (cPLA2).…”

Matrine: A Promising Natural Product With Various Pharmacological Activities

“…Matrine can inhibit the proliferation and migration of pancreatic cancer Panc-1 cells, induce ROS production, and induce apoptosis, which is related to ROS/NF-kB/matrix metalloproteinase (MMP) pathway (Huang and Xin, 2018). Matrine can also inhibit the proliferation of KRAS-mutated pancreatic cancer MIAPACA2 and 8988T cells, inhibit autophagy by downregulating STAT3, and inhibit mitochondrial energy production (Cho et al, 2018). Ma Y. et al (2015) reported that matrine downregulates the expression of MT1-MMP via Wnt signaling pathway and inhibits pancreatic cancer cell migration and invasion.…”

<p>Anti-Tumor Activities of Bioactive Phytochemicals in <em>Sophora flavescens</em> for Breast Cancer</p>

“…For years, MT has been reported to have promising pharmaceutical efficacies for various cancer cells, such as acute myeloid leukaemia, nasopharyngeal Carcinoma, hepatocellular carcinoma, cervical cancer, colorectal cancer, bladder cancer, prostate cancer, pancreatic cancer. [43][44][45][46][47][48][49][50][51][52][53][54] However, the antitumor function about the molecular mechanism of MT still remains unclear. Like other extracts of botanicals, it has some moderate side effects, such as toxicity to the central nervous, coupled with system low water solubility, bioactivity and bioavailability.…”