PAC exhibits potent anti‐colon cancer properties through targeting cyclin D1 and suppressing epithelial‐to‐mesenchymal transition

Abstract

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide. Although response rates and overall survival have been improved in recent years, resistance to multiple drug combinations is inevitable. Therefore, the development of more efficient drugs, with fewer side effects is urgently needed. To this end, we have investigated in the present report the effect of PAC, a novel cucumin analogue, on CRC cells both in vitro and in vivo. We have shown that PAC induces apoptosis, mainly via the internal mitochondrial route, and inhibits cell proliferation through delaying the cell cycle at G2/M phase. Interestingly, the pro-apoptotic effect was mediated through STAT3-dependent down-regulation of cyclin D1 and its downstream target survivin. Indeed, change in the expression level of cyclin D1 modulated the expression of survivin and the response of CRC cells to PAC. Furthermore, using the ChIP assay, we have shown PAC-dependent reduction in the binding of STAT3 to the cyclin D1 promoter in vivo. Additionally, PAC suppressed the epithelial-to-mesenchymal process through down-regulating the mesenchymal markers (N-cadherin, vimentin and Twist1) and inhibiting the invasion/migration abilities of the CRC cells via repressing the pro-migration/invasion protein kinases AKT and ERK1/2. In addition, PAC inhibited tumor growth and repressed the JAK2/STAT3, AKT/mTOR and MEK/ERK pathways as well as their common downstream effectors cyclin D1 and survivin in humanized CRC xenografts. Collectively, these results indicate that PAC has potent anti-CRC effects, and therefore could constitute an effective alternative chemotherapeutic agent, which may consolidate the adjuvant treatment of colon cancer.

Synergistic Anti-proliferative Effects of Cucurbitacin I and Irinotecan on Human Colorectal Cancer Cell Lines

“…In addition to JAK/STAT pathway, MEK/ERK and PI3K/AKT signaling pathways also associated with tumorigenesis and prognosis of colorectal cancer. Consequently, there are three important signaling pathways in colorectal cancer tumorigenesis and prognosis involving JAK2/STAT3, PI3K/Akt/mTOR, and RAS/MEK/ERK pathways [39]. In the present study we have shown that combination of irinotecan and cucurbitacin I has inhibitory effect on JAK2/STAT3 pathway which is one of these three pro-metastatic pathways on colorectal cancer cell lines.…”

“…Moreover, some drug combinations show strong synergism that helps to achieve the same therapeutic effect with lower dose and, hence, less toxicity [34][35][36][37][38][39][40][41][42]. Some reports have shown that cucurbitacins show a synergistic effect with chemotherapeutic agents that are already established in the treatment of human cancers [38][39][40][41][42].…”

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges

“…PAC administration inhibited the growth of subcutaneously implanted MDA-MB-231 breast cancer cells in a nude mice model and was associated with downregulation of AKT and ERK1/2, up-regulated E-cadherin, while it down-regulated N-cadherin, vimentin, and TWIST1 [195,196]. Similarly, in CRC, PAC was shown to suppress EMT and was associated with concomitant suppression of MEK/ERK, JAK2/STAT3, and AKT/mTOR signaling pathways both in vitro and in vivo [197]. PAC inhibited colorectal tumor growth in a nude mice model [197].…”

“…Similarly, in CRC, PAC was shown to suppress EMT and was associated with concomitant suppression of MEK/ERK, JAK2/STAT3, and AKT/mTOR signaling pathways both in vitro and in vivo [197]. PAC inhibited colorectal tumor growth in a nude mice model [197].…”

FGFR1 regulates proliferation and metastasis by targeting CCND1 in FGFR1 amplified lung cancer

“…More than 35 distinct transcription factors are regulated by CCND1 expression [22]. The oncogenic roles of the CCND1 have been demonstrated in various studies, with numerous human cancers including thyroid breast, LADC, liver, colon, and prostate, overexpress CCND1 [23][24][25][26][27]. Notably, 1/3 of FGFR1-amplified tumors harbor amplification of CCND1 in breast cancer [28,29].…”