MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and understanding its underlying molecular mechanisms is crucial for the development of therapeutic strategies. The mitogen-activated protein kinase-kinase 3 (MKK3) is a specific activator of p38 MAP kinases (p38 MAPKs), which contributes to the regulation of several cellular functions, such as proliferation, differentiation, apoptosis as well as response to drugs. At present, the exact MKK3/p38 MAPK pathway contribution in cancer is heavily debated because of its pleiotropic function. In this work, we retrospectively explored the prognostic and pathobiologic relevance of MKK3 in a cohort of CRC patients and assessed MKK3 molecular functions in a panel of CRC lines and colonocytes primary cultures. We found increased MKK3 levels in late-stage CRC patients which correlated with shorter overall survival. Herein, we report that the MKK3 targeting by inducible RNA interference univocally exerts antitumor effects in CRC lines but not in primary colonocytes. While MKK3 depletion per se affects growth and survival by induction of sustained autophagy and death in some CRC lines, it potentiates response to chemotherapeutic drug 5-fluorouracil (5-FU) in all of the tested CRC lines in vitro. Here, we demonstrate for the first time that in CRC the MKK3 specifically activates p38delta MAPK isoform to sustain prosurvival signaling and that such effect is exacerbated upon 5-FU challenge. Indeed, p38delta MAPK silencing recapitulates MKK3 depletion effects in CRC cells in vitro and in vivo. Overall, our data identified a molecular mechanism through which MKK3 supports proliferation and survival signaling in CRC, further supporting MKK3 as a novel and extremely attractive therapeutic target for the development of promising strategies for the management of CRC patients.

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

“…We recently demonstrated that p38δ MAPK, mainly activated by upstream MKK3 kinase in CRC, is further activated by 5-FU, thus hampering its efficacy. The p38δ MAPK inhibition by RNAi improves 5-FU response in CRC lines in vitro and in vivo [18]. Of interest with identical experimental CRC models, the pharmacologic p38α MAPK inhibition (SB203580) exerts protective effects against 5-FU induced apoptosis, suggesting that, in addition to an MKK3/p38δ MAPK pro-survival signaling, a p38α MAPK pro-apoptotic signaling is triggered by 5-FU and possibly mediated by a different upstream kinase (likely, MKK6) [19].…”

“…Indeed, genetic depletion of the p38α MAPK isoform (main target of the SB203580) also exerted protective effects against 5-FU induced apoptosis, confirming that p38α MAPK isoform activation mediates pro-apoptotic signaling in response to this chemotherapeutic agent [12], and hence, arguing against the use of p38 MAPK inhibitors as perspective therapeutic agents to be exploited in combination with chemotherapy [23]. More recently, it was demonstrated that, in response to 5-FU exposure, CRC cells display activation of the p38δ MAPK isoform and that depletion of either p38δ MAPK or its upstream kinase MKK3 (MAP2K3) univocally exerts antitumor effects [18]. This observation highlights the importance of isoform-specific activation of the p38 MAPK in mediating different effects and, in fact, provides a possible explanation for the contradictive effects reported for p38 MAPK activation in response to 5-FU.…”

“…However, when translated into clinical practice, p38 MAPK manipulation did not meet the high expectations. We recently reported [18], at least in CRC, that 5-FU exposure induces p38δ MAPK isoform activation sustaining pro-survival signals; however, in parallel, others and us observed that the p38α MAPK isoform is also activated by 5-FU, and that this mediates the anti-tumor effect [12,19]. This simultaneous triggering of both anti-tumor and pro-survival effects goes along well with the pleiotropic role that the p38 MAPK signaling also exerts in physiological conditions.…”

TRIM67 inhibits tumor proliferation and metastasis by mediating MAPK11 in Colorectal Cancer

“…To gain insights into mechanism of TRIM67 as a CRC suppressor, RNA sequencing in present study revealed that TRIM67 targeted MAPK11 to play a tumor suppressor role in CRC cells. Studies have showed that MAPK signaling pathways are involved in tumor progression, cell growth, cell proliferation, and metastasis in CRC [19][20][21][22]. The MAPK pathways include extracellularregulated kinases 1 and 2 (ERK1/ERK2), c-Jun N-terminal kinases (JNKs), p38 (MAPK11-14), and extracellular-regulated kinase 5 (ERK5).…”

The miR-19b-3p/MAP2K3/STAT3 Feedback Loop Regulates Cell Proliferation and Invasion in Esophageal Squamous Cell Carcinoma

“…The role of MAP2K3 in cancer progression is contradictory. MAP2K3 has been shown to enhance tumor progression, and the loss of MAP2K3 results in inhibition of cellular proliferation and increased response of tumor cells to chemotherapeutic drugs in vivo [5,12,13]. However, recent research has demonstrated that the loss of MAP2K3 copy number occurs in NSCLC and that MAP2K3 inhibits cell proliferation and promotes cellular senescence in hepatocellular carcinoma, breast cancer and melanoma [7,[14][15][16][17].…”