STAT3 Is Necessary for Proliferation and Survival in Colon Cancer–Initiating Cells

Lin, Li; Liu, Aiguo; Peng, Zhen; Lin, Huey‐Jen; Li, Pui-Kai; Li, Chenglong; Lin, Jiayuh

doi:10.1158/0008-5472.can-10-4660

Cited by 272 publications

(224 citation statements)

References 42 publications

Supporting

Mentioning

209

Contrasting

Order By: Relevance

“…This was further supported by the findings that carnosol diminished STAT3 DNA binding and STAT3-reporter gene activity, thereby reducing the expression of D-series cyclins and survivin, which are STAT3 target gene products (13,35). While, survivin inhibits Fas-mediated apoptosis in cancer cells (36), cyclins promote cell proliferation (15). Thus, the reduced expression of survivin and D-series cyclins by carnosol is associated with the induction of apoptosis by this compound.…”

Section: Discussionmentioning

confidence: 74%

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

Park

Chae

Kim

et al. 2014

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Carnosol, an active constituent of rosemary, has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. In the present study, we found that carnosol significantly reduced the viability of human colon cancer (HCT116) cells in a concentration-and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase (PARP). Incubation with carnosol elevated the expression of Bax and inhibited the levels of Bcl-2 and Bcl-xl. Carnosol induced expression of p53 and inhibited that of murine-double minute-2 (Mdm2). Moreover, carnosol generated reactive oxygen species (ROS), and pretreatment with N-acetyl cysteine abrogated carnosol-induced cleavage of caspase-3 and PARP. The constitutive phosphorylation, the DNA binding and reporter gene activity of signal transducer and activator of transcription-3 (STAT3) was diminished by treatment with carnosol. To further elucidate the molecular mechanisms of STAT3 inactivation, we found that carnosol attenuated the phosphorylation of Janus-activated kinase-2 (Jak2) and Src kinase. Pharmacological inhibition of Jak2 and Src inhibited STAT3 phosphorylation. Furthermore, carnosol attenuated the expression of STAT3 target gene products, such as survivin, cyclin-D1, -D2, and -D3. Taken together, our study provides the first report that carnosol induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway. IntroductionDespite a declining trend worldwide, colorectal cancer still remains as the third most common cancer among men and the second in women (1,2). More than one million new cases of colorectal cancer are diagnosed every year (3). A wide variety of natural compounds derived from edible plants have been shown to prevent colon carcinogenesis (4). Carnosol, a diterpene present in rosemary (Rosmarinus officinalis), has been reported to prevent the development of intestinal tumors in APC (adenomatous polyposis coli) min+/+ mice (5) and to induce apoptosis in human colon cancer (COLO 205) cells (6). However, the molecular mechanisms underlying the chemopreventive and/or chemotherapeutic effects of carnosol in colon cancer are yet to be fully elucidated. We, therefore, attempted to investigate the effects of carnosol on human colon cancer (HCT116) cells and to elucidate its underlying mechanisms.One of the hallmarks of cancer is the evasion of tumor cells from apoptosis (7). Numerous naturally occurring polyphenols inhibit proliferation and induce apoptosis in various cancer cells (8). Apoptosis is induced by two cellular mechanisms: intrinsic (mitochondria-dependent) and extrinsic (death receptor-mediated) signaling (9). The intrinsic pathway of apoptosis involves the depolarization of mitochondrial membrane, release of cytochrome c, sequential activation of caspase-9, ...

show abstract

Section: Discussionmentioning

confidence: 74%

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

Park

Chae

Kim

et al. 2014

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…In endometrial cancer, high expression levels of the inflammatory cytokine IL6 and of its downstream effector STAT3 are often found in therapyinsensitive endometrial cancers where they represent poor prognosis indicators (11,20). Notably, several studies implicate both IL6 and STAT3 as important regulators of self-renewal of CSCs in a broad spectrum of tumor types (31)(32)(33)(34)(35)(36). IL6 represents the link between inflammation and malignant transformation, as it activates the NF-kB pathway that, on its turn, promotes IL6 expression in a positive feedback loop (37).…”

Section: Discussionmentioning

confidence: 99%

IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden

et al. 2015

View full text Add to dashboard Cite

Cancer stem-like cells (CSC) may be critical to maintain the malignant behavior of solid and hematopoietic cancers. Recently, patients with endometrial cancer whose tumors expressed high levels of aldehyde dehydrogenase (ALDH), a detoxifying enzyme characteristic of many progenitor and stem cells, exhibited a relative reduction in survival compared with patients with low levels of ALDH. Given evidence of its role as a CSC marker, we hypothesized that high level of ALDH activity (ALDH hi ) in a tumor might positively correlate with the presence of stem-and progenitor-like tumor cells in this disease setting.

show abstract

“…54 Briefly, cells were trypsinized to single cells at a concentration of 0.5-1.0£10 6 and subsequently suspended in ALDEFLUOR assay buffer containing ALDH substrate and then incubated for 45 minutes at 37 C. In all experiments, the ALDEFLUOR-stained cells treated with diethylaminobenzaldehyde(DEAB), a specific ALDH inhibitor, served as ALDH-negative controls. The Flow cytometer setup and data acquisition were followed by Aldehyde Dehydrogenase Based Cell Detection Kit (ALDEFLUOR TM , 01700).…”

Section: Aldefluor Assay and Flow Cytometrymentioning

confidence: 99%

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

Xu¹,

Sun²,

Qin

et al. 2015

Cell Cycle

View full text Add to dashboard Cite

Keywords: breast cancer stem cells, KRas, let-7a, mammosphere formation capacity, MAPK/ERK, NF-kB Abbreviations: BCSCs, breast cancer stem cells; MFE, mammosphere-forming efficiency Breast cancer stem cells (BCSCs) have the greatest potential to maintain tumorigenesis in all subtypes of tumor cells and were regarded as the key drivers of tumor. Recent evidence has demonstrated that BCSCs contributed to a high degree of resistance to therapy. However, how BCSCs self renewal and tumorigenicity are maintained remains obscure. Herein, our study illustrated that overexpression of let-7a reduced cell proliferation and mammosphere formation ability of breast cancer stem cells(BCSCs) in a KRas-dependent manner through different pathways in vitro and in vivo. To be specific, we provided the evidence that let-7a was decreased, and reversely the expression of KRas was increased with moderate expression in early stages (I/II) and high expression in advanced stages (III/IV) in breast cancer specimens. In addition, the negative correlation between let-7a and KRas was clearly observed. In vitro, we found that let-7a inhibited mammosphere-forming efficiency and the mammosphere-size via NF-kB and MAPK/ERK pathway, respectively. The inhibitory effect of let-7a on mammosphere formation efficiency and the size of mammospheres was abolished after the depletion of KRas. On the contrary, enforced expression of KRas rescued the effect of let-7a. In vivo, let-7a inhibited the growth of tumors, whereas the negative effect of let-7a was rescued after overexpressing KRas. Taken together, our findings suggested that let-7a played a tumor suppressive role in a KRas-dependent manner.

show abstract

STAT3 Is Necessary for Proliferation and Survival in Colon Cancer–Initiating Cells

Cited by 272 publications

References 42 publications

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

Contact Info

Product

Resources

About