Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition

Abstract

Tumor microenvironment is fundamental for cancer progression and chemoresistance. Among stromal cells tumor-associated macrophages (TAMs) represent the largest population of infiltrating inflammatory cells in malignant tumors, promoting their growth, invasion, and immune evasion. M2-polarized TAMs are endowed with the nitric oxide (NO)-generating enzyme inducible nitric oxide synthase (iNOS). NO has divergent effects on tumors, since it can either stimulate tumor cells growth or promote their death depending on the source of it; likewise the role of iNOS in cancer differs depending on the cell type. The role of NO generated by TAMs has not been investigated. Using different tumor models in vitro and in vivo we found that NO generated by iNOS of M2-polarized TAMs is able to protect tumor cells from apoptosis induced by the chemotherapeutic agent cisplatin (CDDP). Here, we demonstrate that the protective effect of NO depends on the inhibition of acid sphingomyelinase (A-SMase), which is activated by CDDP in a pathway involving the death receptor CD95. Mechanistic insights indicate that NO actions occur via generation of cyclic GMP and activation of protein kinase G (PKG), inducing phosphorylation of syntaxin 4 (synt4), a SNARE protein responsible for A-SMase trafficking and activation. Noteworthy, phosphorylation of synt4 at serine 78 by PKG is responsible for the proteasome-dependent degradation of synt4, which limits the CDDP-induced exposure of A-SMase to the plasma membrane of tumor cells. This inhibits the cytotoxic mechanism of CDDP reducing A-SMase-triggered apoptosis. This is the first demonstration that endogenous NO system is a key mechanism through which TAMs protect tumor cells from chemotherapeutic drug-induced apoptosis. The identification of the pathway responsible for A-SMase activity downregulation in tumors leading to chemoresistance warrants further investigations as a means to identify new anti-cancer molecules capable of specifically inhibiting synt4 degradation.

Comprehensive analysis of microRNA‐messenger RNA regulatory network in gemcitabine‐resistant bladder cancer cells

“…Chemotherapeutic drugs could induce oxidative stress not only contributed to DNA damage and cell cycle arrest, but also was associated with chemoresistance. 37 Together, oxidative stress response has a significant role in chemotherapy resistance. In epithelial ovarian cancer cell lines, acquisition of specific point mutations in key redox enzymes after chemotherapeutics resulted in a boost of oxidative stress and application of antioxidant could regain high sensitivity to chemotherapy.…”

Reactive Oxygen and Nitrogen Species–Induced Protein Modifications: Implication in Carcinogenesis and Anticancer Therapy

“…Prolonged * NO production by iNOS promoted angiogenesis and oral squamous cell carcinoma progression (19). In addition, * NO generation by tumor-associated macrophages prevented tumor cells apoptosis and caused chemoresistance to cisplatin (20). However, in breast, colorectal, epidermoid, head, and neck tumors decrease in tetrahydrobiopterin level causes NOS uncoupling and production of O 2 * À and NOO : instead of NO * to promote tumorigenesis (21).…”

Modulation of the formation of active forms of nitrogen by ingredients of plant products in the inhibition of carcinogenesis

“…Снижение функциональной активности клеток неспецифического иммунитета некоторыми авторами рассматривается как необходимое условие развития опухоли и метастазов [63]. Однако последние экспериментальные данные показывают, что NO, источником которого является iNOS в опухолеассоциированных макрофагах, способствует усилению резистентности опухоли к терапии цисплатином, и в этом случае подавление синтеза NO ингибиторами, возможно, улучшит результаты химиотерапии [64]. Следует указать на побочные эффекты при использовании малоселективных ингибиторов iNOS, которые могут изменять активность других изоформ NOS -эндотелиальной и нейрональной, нарушая их жизненно важные функции [52].…”