Inhibition of HER2-integrin signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression

Abstract

HER2, an oncogenic receptor is overexpressed in about 25-30% of breast cancer patients. HER2 has been shown to play role in tumor promotion by having cross-talk with multiple oncogenic pathways in cancer cells. Our results show that Cucurbitacin B (CuB), a triterpenoid steroidal compound inhibited the growth of various breast cancer cells with an IC50 ranging from 18-50nM after 48 and 72 h of treatment. Our study also revealed the significant inhibitory effects of CuB on HER2 and integrin signaling in breast cancer. Notably, CuB inhibited ITGA6 and ITGB4 (integrin α6 & integrin β4), which are overexpressed in breast cancer. Furthermore, CuB also induced the expression of major ITGB1and ITGB3, which are known to cause integrin-mediated cell death. In addition, we observed that TGFβ treatment resulted in the increased association of HER2 with ITGA6 and this association was inhibited by CuB treatment. Efficacy of CuB was tested in vivo using two different orthotopic models of breast cancer. MDA-MB-231 and 4T-1 cells were injected orthotopically in the mammary fat pad of female athymic nude mice or BALB/c mice respectively. Our results showed that CuB administration inhibited MDA-MB-231 orthotopic tumors by 55%, and 4T-1 tumors by 40%. The 4T-1 cells represent stage IV breast cancer and form very aggressive tumors. CuB mediated breast tumor growth suppression was associated with the inhibition of HER2/integrin signaling. Our results suggest novel targets of CuB in breast cancer in vitro and in vivo.

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

“…Immuno-precipitation was performed as described by us previously (10,28–30). Briefly, 0.75×10 6 MDA-MB-231 cells were plated in 100mm tissue culture dishes and treated with 6µM PF.…”

“…Accumulating evidence suggests a major role of integrins in cancer. Integrinα6β4 have been implicated in breast cancer progression and metastasis, making it an attractive target for breast cancer therapy (10–13). …”

Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells

“…Furthermore, it enhances the anticancer effects of clinical chemotherapeutic drugs: cisplatin, gemcitabine, methotrexate, docetaxel, and gemcitabine [9][10][11][12]. Documented results also demonstrate that Cuc B potently inhibits the proliferation of breast cancer cell lines both in vitro and in vivo [13][14][15][16][17]. Cuc B suppressed breast cancer cell growth by HER2/integrin signaling, which further led to inhibiting integrin-mediated cell survival through ILK1 and paxillin [14], by disruption of microtubule polymerization and disturbance of nucleophosmin/ B23 translocation [15], and by inhibiting Wnt signaling [18].…”

“…Documented results also demonstrate that Cuc B potently inhibits the proliferation of breast cancer cell lines both in vitro and in vivo [13][14][15][16][17]. Cuc B suppressed breast cancer cell growth by HER2/integrin signaling, which further led to inhibiting integrin-mediated cell survival through ILK1 and paxillin [14], by disruption of microtubule polymerization and disturbance of nucleophosmin/ B23 translocation [15], and by inhibiting Wnt signaling [18]. However, clarifying the exact mechanisms needs further investigation.…”

Cucurbitacin Attenuates Hyperglycemia by Increasing Glut2 Through Pi3k-Pakt in the Hepatocytes of Streptozotocin Induced Diabetic Rats

“…[12] In particular, antiproliferative activity has been found in eight cucurbitacins, including cucurbitacin B, D, E, I, IIa, L, Q, and R. [13,14] Furthermore, the anticancer properties of several variants of cucurbitacins have been observed both in vitro and in vivo. [15][16][17] Cucurbitacin promotes apoptosis in colon cancer tested by tumor models of syngeneic transplanted mice [17] and induces apoptosis in pancreatic cancer cells. [18] These mechanisms indicate that inhibition of the JAK/STAT3 pathway by cucurbitacin may be effective in cancer immunotherapy.…”