Programmed cell death 4 inhibits leptin-induced breast cancer cell invasion

Abstract

Abstract. Obesity is a significant risk factor for post-menopausal women to develop and die from breast cancer. Leptin, an adipokine is produced in high levels in obese individuals, and its receptor is overexpressed in breast tumors and lymph node metastases. Previously, we demonstrated that leptin stimulates breast cancer cell invasion, which is correlated with breast cancer metastasis. Programmed cell death 4 (PDCD4) has been shown to block cancer cell invasion. However, whether PDCD4 blocks leptin-induced breast cancer cell invasion is not known. Here, we report the novel findings that leptin failed to induce invasion in MCF-7 breast cancer cells overexpressing PDCD4 (MCF-7/PDCD4). Tissue inhibitor of metalloproteinase-2 (TIMP-2) was essential to the anti-invasive effect of PDCD4, as leptin stimulated the invasion of MCF-7/ PDCD4 cells pretreated with TIMP-2 siRNA. Furthermore, TIMP-2 knockdown allowed leptin to augment phosphorylation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3, but not that of Jun N-terminal kinases. These data indicate that PDCD4 utilizes TIMP-2 to exert its anti-invasive effect by suppressing leptininduced activation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast tumors may be able to stop obesity-related breast tumor progression and prolong the life of patients. IntroductionBreast cancer is the most frequently diagnosed cancer in women. In 2010, about 207,090 new cases of invasive breast cancer were expected to be diagnosed among women, and about 39,840 women were expected to die from breast cancer. One of the major risk factors for postmenopausal women to develop breast cancer is obesity. Tumors from breast cancer patients with high body mass index are typically of the hormoneresponsive type (1-3). Leptin, a 16-kDa hormone that was discovered as a regulator of body weight and energy balance acting in the hypothalamus (4), is an important hormonal link between obesity and breast cancer. As body weight and fat mass increase, the level of circulating leptin increases (5,6).High expression of leptin and the long/signaling form of leptin receptor have been found in breast tumors (7-11). Leptin-deficient mice have decreased incidence of oncogeneinduced mammary tumors (12). An inhibitor targeted to the leptin receptor suppresses breast tumor formation in vivo (13). High levels of leptin in breast tumors have been correlated with poorer patient prognosis and increased incidence of metastasis (7,10,11). Breast cancer metastasis is directly associated with breast cancer cell invasion. Recently, we showed that leptin stimulates invasion of MCF-7 breast cancer cells by activating Jun N-terminal kinases (JNK), which increase matrix metalloproteinase-2 activity (14).Leptin has also been associated with the development of anti-estrogen resistance. Leptin is a potent modulator of the estrogen receptor signaling pathwa...

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer

“…The invasiveness of HeyA8-MDR and OVCAR-5 cells treated with ZA was determined as previously described (15). Briefly, HeyA8-MDR and OVCAR-5 cells were collected and washed with serum-free media.…”

The role of Pdcd4 in tumour suppression and protein translation

“…Beyond inhibiting tumor promotion, over-expression of PDCD4 cDNA also suppresses tumor invasion or intravasation in many types of cancer cells including breast, colon, liver, gastric, and ovarian cancer (Gonzalez-Villasana et al 2012, Leupold et al 2007, Nieves-Alicea et al 2009, Wei et al 2012, Yang et al 2006, Yu et al 2014, Zhang et al 2009). On the other hand, lowering Pdcd4 expression by PDCD4 siRNA or shRNA stimulates invasion in breast, colon, lung, and nasopharyngeal cancer cells (Santhanam et al 2010, Wang et al 2008, Wang et al 2010, Yang et al 2015, Zhen et al 2017).…”

“…While down-regulation of Pdcd4 by delivery of PDCD4 shRNA into the lung of A/J mice enhances CDK4 expression (Hwang et al 2010), indicating that Pdcd4 inhibits cell proliferation and induces apoptosis in mouse lung. In addition, it has shown that Pdcd4 inhibits invasion in breast cancer cells by enhancing the expression of tissue inhibitor of metalloproteinase 2 (TIMP2) (Gonzalez-Villasana et al 2012, Nieves-Alicea et al 2009). The TIMP2 is a natural inhibitor of the matrix metalloproteinases (MMPs), which suppresses cell migration and invasion by preventing penetration of extracellular matrix.…”

miR-181b functions as an oncomiR in colorectal cancer by targeting PDCD4

“…Recent findings indicate that PDCD4 can function as a protein translation suppressor though both eIF4A-dependent or -independent pathways (Yang et al, 2003 ; Yang et al, 2004 ; Singh et al, 2011 ; Wedeken et al, 2011 ). PDCD4 is widely recognized as an important tumor suppressor, as its expression is dramatically downregulated in many cancer types, including CRC (Yang et al, 2006 ), lung cancer (Chen et al, 2003 ), breast cancer (Gonzalez-Villasana et al, 2012 ) and gastric cancer (Guo et al, 2013 ). Several studies have validated that loss of PDCD4 during tumorigenesis promotes cancer cell proliferation (Li et al, 2014 ), metastasis (Yang et al, 2006 ) and inhibits apoptosis (Wang et al, 2010b ).…”