Abstract
The medicinal mushroom Ganoderma lucidum (Reishi) was tested as a potential therapeutic for Inflammatory Breast Cancer (IBC) using in vivo and in vitro IBC models. IBC is a lethal and aggressive form of breast cancer that manifests itself without a typical tumor mass. Studies show that IBC tissue biopsies overexpress E-cadherin and the eukaryotic initiation factor 4GI (eIF4GI), two proteins that are partially responsible for the unique pathological properties of this disease. IBC is treated with a multimodal approach that includes non-targeted systemic chemotherapy, surgery, and radiation. Because of its non-toxic and selective anti-cancer activity, medicinal mushroom extracts have received attention for their use in cancer therapy. Our previous studies demonstrate these selective anti-cancer effects of Reishi, where IBC cell viability and invasion, as well as the expression of key IBC molecules, including eIF4G is compromised. Thus, herein we define the mechanistic effects of Reishi focusing on the phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, a regulator of cell survival and growth. The present study demonstrates that Reishi treated IBC SUM-149 cells have reduced expression of mTOR downstream effectors at early treatment times, as we observe reduced eIF4G levels coupled with increased levels of eIF4E bound to 4E-BP, with consequential protein synthesis reduction. Severe combined immunodeficient mice injected with IBC cells treated with Reishi for 13 weeks show reduced tumor growth and weight by ∼50%, and Reishi treated tumors showed reduced expression of E-cadherin, mTOR, eIF4G, and p70S6K, and activity of extracellular regulated kinase (ERK1/2). Our results provide evidence that Reishi suppresses protein synthesis and tumor growth by affecting survival and proliferative signaling pathways that act on translation, suggesting that Reishi is a potential natural therapeutic for breast and other cancers.
Highlights
Inflammatory breast cancer (IBC) is a rare, aggressive and lethal type of breast cancer that involves hyperactivation of protein synthesis pathways
To test whether Reishi treatment affects the expression of genes involved in the PI3K/AKT/ mammalian target of rapamycin (mTOR) pathway, we performed PI3K/AKT signaling RT2 Profiler PCR arrays in SUM-149 cells treated with vehicle or 0.5 mg/mL Reishi for 3 hours
We show that Reishi reduces the expression of RAS, and of p-ERK1/2 without affecting total ERK1/2 levels (Figure 4B, 4C). These results provide evidence that the various compounds found in Reishi, which have yet to be isolated, have an inhibitory anticancer effect manifested by reduced tumor growth, gene expression, protein synthesis and concomitant inhibition of the mTOR and MAPK pathways showing relevant therapeutic implications in IBC
Summary
Inflammatory breast cancer (IBC) is a rare, aggressive and lethal type of breast cancer that involves hyperactivation of protein synthesis pathways. In IBC, cancer cells block dermal lymphatics of the breast causing an inflammatory phenotype. IBC lethality derives from generation of tumor emboli, which are non-adherent cell clusters that rapidly spread into the dermal lymphatics by a form of continuous invasion known as passive metastasis. Despite improvements in survival and outcomes for breast cancer generally over the last 20 years, patients with IBC continue to have a poorer prognosis with 5year survival rates of 50% [1], whereas the average comparable rates for patients with non-inflammatory breast cancers are 70% to 80%. The systemic treatment utilized to treat IBC causes generalized destructive effects affecting both cancerous and non-cancerous cells, new therapeutic strategies are highly desirable to improve the prognoses of women with inflammatory carcinoma
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